A Specialist Periodical Report
Organophosphorus Chemistry Volume 2
A Review of the Literature Published between July 1...
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A Specialist Periodical Report
Organophosphorus Chemistry Volume 2
A Review of the Literature Published between July 1969 and June 1970
SenioGReporter
S. Trippett, Department of Chemistry, The University, Leicester Reporters R. S. Davidson, The University, Leicesfer N. Hamer, Cambridge Universify
D. W. Hutchinson, Universify of Warwick R. Keat, Glasgow Universify
J. A. Miller, Universify of Dundee D. J. H. Smith, The Universify, Leicesfer
J. C. Tebby, Norfh Staffordshire Polytechnic B. J. Walker, Queen’s University of Belfast
SBN : 85186 016 8 @ Copyright 1971
The Chemical Society Burlington House, London, W I V OBN
Orgunic formulae composed by John Wright’s Symbolset method
Printed in Great Britain by John Wright and Sons Ltd. at The Stonebridge Press, Bristol BS4 SNU
Foreword
The comments that we have so far received on the first volume of ‘Organophosphorus Chemistry’ have encouraged us to continue with the same structure in this second volume. The original Reporters were in some cases almost overwhelmed by the volume of work published in their areas and new Reporters have joined us this year. Overlapping has thus become a greater problem; some has been eliminated but much of necessity remains. S. T.
Contents
Chapter 1 Phosphines and Phosphonium Salts By D. J. H. Smith I Phosphines 1 Preparation A From Halogenophosphine and Organometallic Reagent B From Metallated Phosphines C By Reduction D By the Radical Addition of P-H to Olefins 2 Reactions A Nucleophilic Attack on Carbon (i) Activated Olefins (ii) Activated Acetylenes (iii) Carbonyls etc. (iv) Miscellaneous B Nucleophilic Attack on Halogen C Nucleophilic Attack on Other Atoms D Miscellaneous
1
7 7 7 8 11 11 12 14 16
I I Phosphonium Salts 1 Preparation 2 Reactions A Alkaline Hydrolysis B Additions to Vinylphosphonium Salts C Miscellaneous
I II Phosphorins and Phospholes 1 Phosphorins A Preparation B Structure C Reactions 2 Phospholes
18 21 21 25
25
26 26 28 28
28
vi
Contents
Chapter 2 Quinquecovalent Phosphorus Compounds By S. Trippeff 1 Pseudorotation
29
2 2,2’-Biphenylylenephosphoranes
30
3 1,3,2-Dioxaphospholens
31
4 1,3,2-Dioxaphospholans
34
5 1,3,2-0xazaphospholans
36
6 1,2-0xaphospholens
36
7 Miscellaneous
38
Chapter 3 Halogenophosphines and Related Compounds By J. A. Miller 1 Halogenophosphines A Preparation B Reactions (i) NucIeophilic Attack at Phosphorus (ii) Electrophilic Attack at Phosphorus (iii) Miscellaneous
41 41 43 43 45 46
2 Halogenophosphoranes A Structure and Spectra B Reactions
48 48 49
3 Phosphines Containing a P-X Bond (X = Si, Ge, Sn, or Pb) A Preparation B Reactions
52 52 53
Chapter 4 Phosphine Oxides By J. A. Miller 1 Preparation A Using Organometallic or Complex Hydride Reagents B From Alkyl Phosphinites C By Addition Reactions of Secondary Phosphine Oxides (i) To Carbonyl (ii) To other Multiple C=X Bonds D Miscellaneous
55
55 56
57 57 58 59
vii
Contents
2 Reactions Nucleophilic Reactions of P=O and P=S groups Electrophilic Reactions Reactions not involving P=O and P=S Groups Miscellaneous
60 60 61 62 66
Chapter 5 Tervalent Phosphorus Acids By B. J. Walker 1 Introduction
67
2 Phosphorous Acid and its Derivatives A Nucleophilic Reactions (i) Attack on Saturated Carbon (ii) Attack on Unsaturated Carbon (iii) Attack on Oxygen (iv) Attack on Halogen (v) Attack on Hydrogen B Electrophilic Reactions C Rearrangements D Cyclic Esters of Phosphorous Acid E Miscellaneous Reactions
67 67 68 78 85 86 86 88 89 91
3 Phosphonous Acid and its Derivatives
92
4 Phosphinous Acid and its Derivatives
93
67
Chapter 6 Quinquevalent Phosphorus Acids By N. K. Hamer 1 Phosphoric Acid and its Derivatives
A Synthetic Methods B Solvolyses of Phosphoric Acid Derivatives C Reactions
94 94
99 104
2 Phosphonic and Phosphinic Acids and Derivatives A Synthetic Methods B Solvolyses of Phosphonic and Phosphinic Esters C Reactions of Phosphonic and Phosphinic Acid Derivatives
108 108 112
3 Miscellaneous
117
115
...
Contents
Vlll
Chapter 7 Phosphates and Phosphonates of Biochemical Interest By D. W. Hutchinson 1 Mono-, Oligo-, and Poly-nucleotides
A Mononucleotides B Nucleoside Polyphosphates C Oligo- and Poly-nucleotides D Nucleoside Thiophosphates E Physical Methods and Analytical Techniques 2 Coenzymes and Cofactors
A B C D
Phosphoenol Pyruvate Nicotinamide Coenzymes Nucleoside Diphosphate Sugars Other Nucleotide Coenzymes
3 NaturalIy Occurring Phosphonic Acids
A Aminophosphonic Acids B Phosphonomycin
119 119 128 130 134 136 137 137 138 139 142 143 143 144
4 Oxidative Phosphorylation
145
5 Sugar Phosphates A Pentoses B Hexoses
146 146 147
6 Inositol Phosphates and Phospholipids A Inositol Phosphates B Phospholipids
148 148 149
7 Enzymology
150
8 Other Compounds of Biochemical Interest
153
Chapter 8 Ylides and Related Compounds By S. Trippett 1 Methylenephosphoranes A Preparation B Reactions (i) Inorganic Reagents (ii) Halides (iii) Carbonyls (iv) Miscellaneous
156 156 159 159 160 164 170
ix
Contents 2 Phosphoranes of Special Interest
173
3 Selected Applications of the Wittig Olefin Synthesis A Natural Products (i) Prostaglandins (ii) Isoprenoids (iii) Miscellaneous B Carbohydrates C Miscellaneous
175 175 175 175 179 180 181
4 Synthetic Applications of Phosphonate Carbanions
183
5 Ylide Aspects of Iminophosphoranes
187
Chapter 9 Phosphazenes By R. Keat 1 Introduction
191
2 Synthesis of Acyclic Phosphazenes A From Phosphorus Amides B From Carbon Amides C From Sulphur Amides D From Silicon-Nitrogen Compounds E Other Methods
191 191 194 197 198 199
3 Properties of Acyclic Phosphazenes
202 202 205
A Chemical B Physical
4 Synthesis of Cyclic Phosphazenes
206
5 Chemical Properties of Cyclic Phosphazenes A Addition Compounds B Amino-derivatives C Aryl Derivatives D Aryloxy- and Alkoxy-derivatives E Mercapto-derivatives
209 209 209 213 214 21 6
6 Polymeric Phosphazenes
216
7 Miscellaneous Physical Measurements
217
8 Molecular Structures of Phosphazenes and Related Compounds determined by Diffraction Methods
219
Contents
X
Chapter 10 Photochemistry, Radicals, and Deoxygenation Reactions By R. S. Davidson 1 Photochemistry
22 1
2 Radical Reactions
225
3 Deoxygenation of Peroxides and Desulphurisation of Sulphides
228
4 Deoxygenation of Nitro- and Nitroso-compounds
230
5 Miscellaneous Deoxygenation Reactions
233
Chapter 11 Physical Methods By J. C. Tebby 1 Nuclear Magnetic Resonance Spectroscopy A Chemical Shifts and Shielding Effects B Studies of Equilibria and Reactions C Pseudorotation D Restricted Rotation E Non-equivalence and Medium Effects F Inversion and Configuration G Spin-Spin Coupling (9 JPP and JPM (ii) JPF (iii) Jpc (iv) l J p ~and 2 J ~ p ~ (v) JPC,H (vi) JPOGH and JPNGH H Paramagnetic Effects
236 236 240 242 244 245 247 249 250 25 1 252 252 252 257 257
2 Electron Spin Resonance Spectroscopy
260
3 Vibrational Spectroscopy A Band Assignments and Structural Elucidation B Stereochemical Aspects C Studies of Bonding
26 1 26 1 264 265
4 Microwave Spectroscopy and Dipole Moments
266
5 Electronic Spectroscopy
267
6 Rotation
269
7 Diffraction
270
xi
Contents 8 Electrochemical Studies
275
9 Mass Spectrometry
276
10 pK, Reaction Rate, and Therrnochemical Studies
280
11 Surface Properties
28 1
1 Phosphines and Phosphonium Salts BY
D. J. H. SMITH
PART I: Phosphines 1 Preparation A. From Halogenophosphine and Organometallic Reagent.-(4-Bromopheny1)magnesium bromide reacts with chlorodiphenylphosphine below 10 "C to yield diphenyl(4-bromopheny1)phosphine (l).l In a similar
77%
synthesis, tris(3-fluoropheny1)- and tris(4-fluorophenyl)-phosphines have been prepared2 from excess of the corresponding Grignard reagent and phosphorus trichloride. Trimesitylphosphine (2) can be obtained from excess mesitylmagnesium bromide and phosphorus trichloride.a However, when the amount of
\ \2PCl,
a
(2)
-/ 3
G. P. Schiemenz, Org. Synth., 1969, 49, 66. R. De Ketelaere, E. Muylle, W. Wanerman, E. Claeys, and C. P. Van der Kelen, Buff. SOC.chim. belges., 1969, 78, 219. B. I. Stepanov, E. N. Karpova, and A. I. Bokanov, Zhur. obshchei Khim., 1969,39,1544.
2
Organophosphorus Chemistry
Grignard reagent is limited, the product obtained is tetramesityldiphosphine (3). A synthesis of phosphines utilising alkyl transfer from boron to phosphorus has been de~cribed.~ No attempt was made to prevent oxidation to phosphine oxides during work-up and hence chlorodiphenylphosphine and tricyclohexylborane yielded the phosphine oxide (4). Ph2PCl
+ (CeH&B
(C6H&ByPPh2CI
Lithioacetylides and diethyl phosphorochloridite give (5), which can be treated further with Grignard reagent to yield dialkyl-( 1-alkyny1)phosphines (EtO),PCl
+ LiCiCR1
-
1
(EtO),P.CiCR1 (5)
RMgx
R = alkyl R1 = alkyl, aryl
R2P*CiCR1 (6)
The reaction of cyclopropyl-lithium with triphenyl phosphite and chlorodiphenylphosphine gave tricyclopropylphosphine and cyclopropyldiphenylphosphine respectively.6 Tertiary phosphines have been prepared by the treatment of alkyl halides with phosphites, phosphinites, or phosphonites in the presence of sodium, e.g. : Pr'C1
+ (PhO)3P
Pr',P
B. From Metallated Phosphines.-The cis-diphosphine (7) has been obtained * from lithium diphenylphosphide and cis-l,2-dichloroethane. PhzPLi
+ ClCH :CHCl cis
THF .___j
Ph2P CH :CH PPhz cis (7) 30%
P. M. Draper, T. H. Chan, and D. N. Harpp, Tetrahedron Letters, 1970, 1687. A. M. Aguiar, J. R. S. Irelan, C. J. Morrow, J. P. John, and G. W. Prejean, J. Org. Chem., 1969,34,2684. A. H. Cowley and J. L. Mills, J. Amer. Chem. Soc., 1969, 91, 2915. I. Hechenbleikner and E. J. Lanpher, U.S.P. 3,470,254. J. P. Mitchener and A. M. Aguiar, Org. Prep. Proced., 1969, 1, 259.
Phosphines and Phosphonium Salts
3
- -
Issleib has shown that alkyl-substituted diphosphines can be prepared by exchange reactions with tetraphenyldiphosphine: Ph,P.PPh,
+ LiPR,
Ph2P.PR2
R,P-PR,
R = alkyl
The base-catalysed addition of secondary phosphines to vinylphosphines and ethynylphosphines has been described.1° The reaction is useful for the preparation of poly(tertiary phosphines) with CH2CH, bridges between phosphorus atoms : PhPH,
-
+ 2PhzP. CH :CH2
KOBut
9
PhP(CHzCHzPPhJ2 90%
An acyl-substituted phosphine has been prepared by the reaction of sodium diphenylphosphide with acetyl chloride.ll Treatment of lithium diethylphosphide with boron trichloride gave the dimer (8),12 but with excess silicon halide1, products of the type (9) were BCI,
+ LiPEt,
-
R,-,Si(PEt,), (9)
[B(PEt,),], (8)
x=l,3 R = Me, H, C1
-
obtained. Similar products may be obtained from lithium diethylphosphide and (methylsily1)diethylphosphine(10).14 Methylsilylphosphines have been (MeSiH,)PEt, (10)
+ LiPEt,
MeSi(PEt,),
prepared from potassium silylphosphides and methyl bromide.16 Alternatively, (methylsily1)phosphine can be made from silyl bromide and (1 1). The reaction of trisodium phosphide with trichlorophenylgermane or
Li A1H (PH Me) (1 1)
10
11
l2 l3 l4 l6
K. Issleib and F. Krech, J. prakt. Chem., 1969, 311, 463. R. B. King and P. N. Kapoor, J . Amer. Chem. SOC.,1969,91,5191. R. G. Kostyanouskii and V. V. Yakshin, Izvest. Akad. Nauk. S.S.S.R., Ser. khirn., 1969,478. G. Fritz and F. Pfannerer, Z . anorg. Chem., 1970, 373, 30. G . Fritz, G . Becker, and D. Kummer, Z . anorg. Chem., 1970, 372, 171. G. Fritz and G. Becker, 2. anorg. Chem., 1970, 372, 180. K . D. Crosbie, C. Glidewell, and F. M. Sheldrick, J. Chem. SOC.( A ) , 1969, 1861.
4
Organophosphorus Chemistry
trichlorophenylsilane yields heptamers,ls whereas reaction with dipotassium phenylphosphide l7 gave the tetramers (1 2). 7PhMC13
+ 7Na,P
_CC__J
(PhMP),
+ 21NaCl Ph I
4RMC13
+
6K,PPh ---+
12KC1
+
M = Si, Ge Ph
Ph
aluminium hydride reduction of ( +)-benzylmethylphenylpropylphosphonium bromide proceeds with racemisation,ls whereas the corresponding arsonium compound gave the arsine with retention of configuration. A convenient synthesis of methylphosphines l9 involves the reduction of dimethyl methylphosphonite with lithium aluminium hydride. The resulting methylphosphine can be converted into di- or tri-methylphosphine with methyl iodide in methanol, depending upon the conditions used.
C. By Reduction.-Lithium
MeP( :O)(OMe),
+ LiAlH,
-
MePH,
Me1 MeOH >
Me,PH-
Me,P
Reduction of the bisphosphonium salts (13a) with sodium hydride 2o results in the cleavage of the bridge, irrespective of the substituents on phosphorus. It is suggested that the reaction proceeds with initial attack of hydride ion at phosphorus to give a phosphorane which subsequently decomposes. However, when lithium aluminium hydride is used the loss of the bridge is competitive with loss of the benzyl group. H-
-
+ + R3P.CHz-CH,*PR3 3.
(1 3 4
HPR3.CH,.CH,-$R3
The same phosphonium salts can also be reduced very efficiently with cyanide ion.,' Ethylenebis(tripheny1phosphonium) bromide was reduced l7 l8 lS 2o
H. Schumann and H. Benda, J. Organometallic Chem., 1970,21, P12. H.Schumann and H. Benda, Angew. Chern. Internat. Edn., 1969,8, 989. L. Horner and M. Ernst, Chem. Ber., 1970,103,318. K.D.Crosbie and G. M. Sheldrick, J . Inorg. Nuclear Chem., 1969,31, 3684. J. J. Brophy and M. J. Gallagher, Austral. J . Chem., 1969,22, 1399. J. J. Brophy and M. J. Gallagher, Austral. J. Chem., 1969,22, 1405.
Phosphines and Phosphonium Salts
5
with 2 moles of potassium cyanide in DMSO to triphenylphosphine and succinonitrile. One mole of cyanide gave the p-cyanoethyl salt (13),
+
+
Ph,P*CH2*CH,*PPh,
Ph3P + NC*CH:CH2
CN____+
CN-
Ph3P
+ + CH:CH*PPh, + HCN
J
+
NC.CH2*CH2*PPhs
.L
NC * CH2 CH, CN indicating that an elimination-addition sequence is the probable reaction pathway. In a studyz2of the mechanism of reduction of phosphine oxides with trichlorosilane Mislow has shown that the stereochemical course of the reduction of benzylmethylphenylphosphine oxide depends upon the base used. Weak bases (pKb > 7) give predominant retention, whereas strong bases (pKb < 5 ) give predominant inversion. Complex formation does not appear to be important, but reduction with inversion proceeds via a product of the base decomposition of the chlorosilane, whether a derived perchloropolysilane or a trlchlorosilyl anion as shown. This work naturally led to the use of hexachlorodisilane for the reduction of acyclic HSiCI,
+
Et3N
-
SiCl;
+
t
Et3NH
phosphine oxides with inversion of c~nfiguration.~~ In contrast, the reduction of phosphetan oxides (14) with hexachlorodisilane proceeds with retention. These reductions are faster than their acyclic analogues and it aa aa
K. Naumann, G. Zon, and K . Mislow, J. Amer. Chem. SOC.,1969, 91, 7012. K. E. DeBruin, G. Zon, K. Naumann, and K. Mislow, J . Amer. Chem. SOC.,1969,91, 7027.
6
Organophosphorus Chemistry
is suggested that the reaction proceeds with nucleophilic attack at phosphorus.
CI,SiO/ 'Ph
CI,Si
/L
'Ph.
However, the desulphurisation of acyclic phosphine sulphides proceeds with retention,24 presumably via attack of the trichlorosilyl anion on the sulphur atom of the intermediate trichlorosilylmercaptophosphonium ion (15). R..
R1--'P=S /
+
Si2Cl,
R,..+ R1-P-S--SiCI,
R2
R2
/
+
SiCI,
(15)
Rl-P: RJ
+
SiC1,-S-SiCl,
Decyldichlorophosphine (16) can be reduced catalytically with hydrogen over palladium in the presence of triethylamine.26
D. By the Radical Addition of P-H to 0lefins.-Dimethyl- and bis(trifluoromethyl)-phosphines yield tertiary phosphines, e.g. (17) and (18), with olefins 26 and trifluoroethylene on U.V. irradiation. Photolysis of MeCH:CHMe
+ (CF,),PH
hU
(CF,),P-CHMeEt
(1 7)
G. Zon, K. E. DeBruin, K. Naumann, and K. Mislow, J . Amer. Chem. SOC.,1969,91, 7023. zs R. E. Hall, A. Kessler, and A. R. McLain, U.S.P., 3,459,808. R. Fields, R. N. Haszeldine, and J. Kirman, J . Chem. SOC.(C), 1970, 197. *' R. Fields, R. N. Haszeldine, and N. F. Wood, J . Chem. SOC.(C), 1970, 744. 24
-
Phosphines and Phosphonium Salts CHF:CF,
+ Me,PH
7 Me,P.CF,*CH,F
+
Me,P.CHF.CHF, (1 8)
ethereal solutions of alkylphosphines with divinyl ether 28 leads to perhydro-ly4-oxaphosphorins (19). R-PH,
4-
CH2=C,H O
CH,=dH
n
hv
Tzz--+R - P Q
R = alkyl
(19)
Phosphine and divinyl ether in the presence of AIBN gave (19; R = H), which could be converted to (19; R = CaH,,) by photolysis in oct-l-ene. The bridged phosphine (20) can be converted to the highly condensed system (21) by photolysis through in contrast to the oxide (see Chapter 10, Section 1). Tricyclic phosphines have also been made30 by irradiation of cyclododeca-ly5,9-triene with a 6oCosource in the presence of phosphine. Treatment of the resulting product with AIBN in hexane gave a mixture of phosphines.
ZJ* (20)
(21) 25%
2 Reactions A. Nucleophilic Attack on Carbon.-(i) Activated Olefins. The reaction of diethylphosphine with a-chloroacrylonitrile at room tenperature and some 8-substituted acrylonitriles in the presence of triethylamine s1 led to diethylphosphinoacrylonitrile (22). In the absence of triethylamine at - 15 "C,a-chloroacrylonitrile gave the phosphine (23). Et,PH
+ XCH:CHCN
Et3N
> Et,P*CH: CH CN (22)
X = C1, SCH2C6H5 Et,PH 28
+ CH,:CCI.CN
-15 OC
Et,P+CH,CHCl.CN (23)
P. Tavs, Angew. Chem. Internat. Edn., 1969, 8, 751. T. J. Katz, J. C.Carnahan, G. M. Clarke, and N. Acton, J . Amer. Chem. Suc., 1970, 92, 734.
*O
R. F. Mason, U.S.P. 3,435,076. K. D. Gundermann and A. Gaming, Chem. Ber.,
1969, 102,3023,
8
Organophosphorus Chemistry
Chlorodiethylphosphine and acrylonitrile gave a 1 : I-adduct which, it is claimed, might have the structure of an epiphosphonium salt (24). Tris(hydroxymethy1)phosphine and acrylonitrile gave the phosphine (25).
+
Et,PCl
CH,: CHCN
CH-CH-CN
\+/
Et
(HOCH,),P
+ CH, :CH-CN
2,
-
CI -
Et
(24)
(NC CH, CH,),P (25)
Addition reactions of fumaric acids and esters with acrylic compounds are catalysed by tricycl~hexylphosphine.~~
1
R02C*CH:CH-COzR
X = CN, C02H, C0,Me
CH2:CX
I
CHC0,R
I
CH2C02R
-
The vinyl phosphonium salt (26) has been isolated from the reaction of trip henylphosphine with trans-/3-bromovinylphenylsulphone.34
-
PhSO, CH :CHBr
+ Ph,P
+
Br CH :CH PPh, -S02Ph (26)
For the reaction of diphenylcyclopropenones with triphenylphosphine see Chapter 8, Section 1A. (ii) Activated Acetylenes. Phosphines and diacylacetylenes have been shown to give 1,2-alkylidenediphosphoranes (27) which are thermally less stable and more reactive than the corresponding phosphoranes
Ph3P
+
Ph,p\
,c-c
Ph(O:)C.CiC.C(:O)Ph
RG
32
8a
36
0 ,CR \
PPh,
R. K. Valetdinov, E. V. Kuznetsov, and S. L. Komissarova, Zhur. obshchei Khim., 1969, 39, 1744. K. Morita and T. Kobayashi, Bull. Chem. SOC.Japan, 1969, 42, 2732. E. G. Kataev and F. R. Tantasheva, Zhur. obshchei Khim., 1969,39,213. M. A. Shaw and J. C. Tebby, J. Chem. SOC.(C), 1970, 5.
Phosphines and Phosphonium Salts
9
stabilised by ester groups. In the same paper an alternative synthesis of the diphosphorane (28) starting from a secondary phosphine was described. This synthesis could not be used to prepare the acyl diphosphoranes (27)
Me
,C0,Me
I
NaHCO,
PhZI’f
CH-CH
\+
MeO,C/
P PI13
21-
I
Me
since the phosphine adds preferentially to the carbonyl group rather than to the acetylenic bond. Bis(dipheny1phosphino)methane (29) with one equivalent of dimethyl acetylenedicarboxylate 36 gave 5H-diphosph(v)ole (30). In contrast to Ph ,P- CH, -P P h
2
3Me 0-
1,2-a1kylidenediphosphoranesone obtains a P=C-P=C conjugation. Variable temperature n.m.r. indicated the presence of two conformers resulting from restricted rotation about one ester group. Spectroscopic evidence indicated that the buff-coloured, unstable solid from the reaction of cis-l,2-bis(diphenylphosphino)ethylene and dimethyl 36
M. A. Shaw, J. C. Tebby, R. S . Ward, and D. H. Williams, J. Chern. Soc. (C), 1970, 504.
10
Organophosphorus Chemistry
acetylenedicarboxylate was the 1,4-diphosph(v)orin (3 l), but the bis-ylide (32) obtained from 1,2-bis(diphenylphosphino)ethane and the same acetylene 37 hydrolyses only slowly in water. Ph2
CO,Me
I/pph2+
I
c (31)
C0,Me
PhZ Ph, P -CH,.CH,-PPh,
+
(:I;::
Me0,C.C E C * C0,Me ---+
PhZ (32)
The structure of the yellow adduct obtained from 1,2,5-triphenylphosphole and dimethyl acetylenedicarboxylate has been shown3* to be the phosphorane (33), and not that previously reported, which rearranges to the cyclic phosphine (34)in refluxing chloroform.
Ph
x
Yh
X = C0,Me
(33)
(34)
Dideuteriated olefins (35) can be prepared from triphenylphosphine and activated acetylenes in the presence of deuterium Ph3P
+
RCiCR'
+
D20
THF
+
Ph,P\ ,C=C,
R Ph3P0
+
D,
/
R1
l ,R1
c=c\
R'
D
(35)
Sodium diphenylphosphide and 1-bromobut-2-yne in liquid ammonia gave 40 (but-2-yny1)diphenylphosphine (36). However, the reaction with
39
A. N. Hughes and S. W. S. Jafry, J . Heterocyclic Chem., 1969, 6, 991. N. E. Waite and J. C. Tebby, J . Chem. SOC.(C), 1970, 386. E. M. Richards, J. C. Tebby, R. S. Ward, and D. H. Williams, J . Chem. Soc. ( C ) ,
4
W. Hewertson and 1. C. Taylor, Chem. Cumm., 1970, 119.
a7
38
1969, 1542. O
Phosphines and Phosphonium Salts
+ BrCH, - C i CMe
Ph,? Ph,P
+ BrCH,.CiCH
11
---+
-
Ph,P. CH2.C i CMe (36)
1
+ CH,-CiCH
Ph2PBr NH,
Ph,PNH,
3-bromoprop- 1-yne yielded propyne and diphenylphosphinoamine with no product from attack on carbon being observed. The corresponding chlorides react by nucleophilic attack on carbon. (iii) Carbony Is, etc. Triphenylphosphine and NN’-di benzoyl-o-benzoquinonedi-imide in benzene 41 gave the benzimidazole (37) which is thought to have arisen as shown. i0
0
I/
... 1 I-I
+
N -C -PI1
Ph,P -
N- C- Ph I/ 0
COPh
I
O;>-Ph
N=C-Ph LJ I+
OPPh,
-
COPh
I
3hp;*N 3Jc
,Ph
(37)
Diethylphosphine reacted with carbon disulphide 42 in the presence of base to yield the diethylphosphoniobisdithioformate (39) whereas the reaction with diphenylphosphine stopped at the phosphinodithioformate (38) stage. RzPH
-
L
(38) R
=
Ph
(39) R
= Et
(iu) Miscellaneous. a-Halogenobenzyl phenyl ketones and triphenylphosphine 43 afford the ketophosphonium halide (40) and/or the enol41 82
43
M. Sprecher and D. Levy, Tetrahedron Letters, 1969, 4957. 0.Dahl, N. C. Gelting, and 0. Larsen, Acta Chem. Scund., 1969, 23, 3369. I. J. Borowitz, P. E. Rusek, and R. Virkhaus, J . Org. Chem., 1969,34, 1595.
12 X
I
Ph-CO-CHPh + Ph3P
-
Organophosphorus Chemistry
+
O-PPh3 X-
I
Ph.CO*CHPh + PhCZCHPh
I
+PPh3XX = Br or C1 (42) X = OS0,Me
(40)
phosphonium salt (41) depending upon the reaction conditions. If a-mesyloxybenzylphenylketone (42)is used, only the ketophosphonium salt is obtained. The formation of the ketophosphonium salt is best explained by a direct displacement of halide ion by phosphorus, while amechanisminvolving attack on halogen followed by recombination of the resulting ion pair is favoured for formation of the enolphosphonium salt. It has been shown 44 that these reactions are not base-catalysed as previously reported, but that the presence of base simply prevents the acid-catalysed debromination reaction. B. Nucleophilic Attack on Halogen.-The scope of the reaction by which alcohols can be converted into halides with tertiary phosphine and perhalogenocarbon has been extended.46 The reaction shows a remarkable tendency to give inversion products 46 even when solvolysis of the corresponding esters is assisted and gives retention products, e.g. (43).
Tributylphosphine and carbon tetrachloride 47 gave a polymeric waxy solid (44) which could be hydrolysed to tributylphosphine oxide. Bu,P
+ CC14
-10
"C
C37H81C14P3
Hzo
+ Bu3P0
(44)
A relatively stable compound (45) was the product of the reaction of tri(chloromethy1)phosphine and chlorine in carbon tetrachl~ride.~~ (ClCH2)3P
+ C12
CCl4
'
(c13c)2pc13 (45)
I4
*s 47 48
m.p. 192°C
I. J. Borowitz, K. C. Kirby, P. E. Rusek, and E. Lord, J. Org. Chem., 1969,34, 2687. D. Brett, I. M. Downie, J. B. Lee, and M. F. S. Matough, Chem. andlnd., 1969, 1017. R. G. Weiss and E. I. Snyder, J. Org. Chem., 1970, 35, 1627. G. Kamai, R. F. Valetdinov, and E. K. Ismagilov, Zhur. obshchei Khim., 1969,39,379. E. S. Kozlov and S. N. Gaidamaka, Zhur. obshchei Khim., 1969, 39, 933.
Phosphines and Phosphonium Salts
13
Highly chlorinated ketones are dechlorinated by trivalent phosphorus compounds 49 to a,p-unsaturated products (46). 0C(CCl2*CCI,),
+ 2Ph3P
____.*
OC(CC1:CCl,), (46)
-
In a related reaction, dehalogenation of 2,2,3-tribromopropionitrilehas been achieved using triphenylpho~phine.~~ BrCH,*CBr,.CN
+ Ph,P
CH,:CBrCN
+ Ph,PBr,
1,ZDibenzoylethane was the major product from the reaction of triphenylphosphine with the epoxyketone (47).61 This interesting compound
presumably arises from a reaction sequence as shown. The other products from the reaction can be visualised as being produced via an intermediate
-i
+
Ph,P
(47)
+ Ph,P
5%
0-
I
Ph-CO-CH-C-CH,Br I
Ph. CO. CH :CH-CO-Ph
I
I
Ph
+ Ph. CO.CH,Br
1
Ph. CO. CH :PPh, 8%
Phd'
+
Ph. CO.CH,*PPh, Br30%
phosphonium alkoxide formed by initial attack at carbon. phosphite and (47), however, gave the phosphonate (48). 48
s1
K. Pilgram and H. Ohse, J . Org. Chem., 1969, 34, 1592. K. C. Pande and G. Trampe, J . Org. Chem., 1970,35, 1169. A. Padwa and D. Eastman, J . Org. Chem., 1970,35, 1173.
Triethyl
Organophosphorus Chemistry
14 (47)
---+
-I- (EtO),P
‘’‘’c&l’’’ H 0 CH,P(OEt),
li
0
(48)
Borowitz 44 has shown that a-halogenoketones can be dehalogenated with diphenylphosphine. The reaction is not acid-catalysed as is the reaction with triphenylphosphine. A reaction mechanism involving a six-centred transition state has been proposed. Evidence for this includes a Hammett p value of -0.74 and the fact that sterically hindered ketones do not react any slower than unhindered ones.
C. Nucleophilic Attack on Other Atoms.-A Hammett plot of the rates of reaction of triphenylphosphine with ozonides of substituted styrenes 5 2 gave p = +Om72 There was no significant isotope effect in this reaction, which suggests the formation of an unstable phosphorane (49) in the ratedetermining step.
p-0 \
ArHC,
,CH, 0
4- Ph,P
-
Ph, 0-P, I 0 ArHC, 1 CH,
ArCHO
+
HCHO
+
(49)
Ph, P
Dialkyl t-butyl phosphates (50) can be prepared in low yield 53 from the reaction of triphenylphosphine with the corresponding dialkyl t-butyl peroxyphosphates. (RO),P(: 0)* 0 0* But
+ Ph3P
(RO),P( :0) OBut
+ Ph,PO
(50)
Differences in the reactions of tri(o-toly1)phosphine and the meta- and The latter compounds gave phosphine para-isomers have been oxide upon reaction with thionyl chloride, whereas tri(o-toly1)phosphine gave phosphine oxide and sulphide. Tri(o-toly1)phosphine produced the 52 6s 64
J. Carles and S. Fliszar, Canad. J . Chem., 1970, 48, 1309. G . Sosnovsky, E. H. Zaret, and K. D. Schmidt, J , Org. Chem., 1970, 35, 336. S . I. A. El Sheikh, B. C. Smith, and M. E. Sobeir, Angew. Chem. Infernat. Edn., 1970, 9, 308.
Phosphines and Phosphonium Salts
15
compound (5 1) 'stabilised by specific attractions between o-methyl groups and ligands' upon reaction with liquid sulphur dioxide. The other isomers were unreactive. R3P
+ 2SOC1,
-
R,PO
+ S2C1, + (R,PCI,)
R = p-CHS.C,H,,
m-CH,*C,H,
-
R3P0
A complex mixture is obtained from benzotrifuroxan (52) and triphenylphosphine,66containing five compounds whose structures were elucidated by X-ray crystallography.66
Triphenylphosphine reacted with thiodehydrogliotoxin (53) 67 to give the disulphide (54) with retention of configuration at the asymmetric carbon atoms. However, the disulphide gave the monosulphide (55) more slowly and with inversion of configuration of the asymmetric carbon atoms as judged by circular dichroism. Desulphurisation of trisulphides obviously occurs preferentially at the sulphur-bonded sulphur atom.
OH
-
CH,OH (53)
(54)
*.
"
CH2OH
i
slow Ph,P
CH,OH (55)
56
57
A. S. Bailey, J. M. Peach, C. K. Prout, and T. S. Cameron, J, Chem. Soc. (C), 1969, 2277. T. S. Cameron and C. K. Prout, J . Chem. SOC.(C), 1969,2281,2285,2289,2292,2295. S. Safe and A. Taylor, Chem. Comm., 1969, 1466.
16 Organophosphorus Chemistry A 1,3-dipole (56) is thought to be the correct structure for the product
-
from triphenylphosphine and dimethyl azodicarboxylate.s8 Ph,P
+
MeO,C.N:N.CO,Me
+
Ph,P,
,N-G-CO2Me MeOK (56)
A pyrazole (57) was isolated from the reaction of (56) with dimethyl acetylenedicarboxylate.
(‘56)
+ MeO,C*C-C.CO,Me
>-
C0,Me I + N Ph3P-N’ ‘C-C0,Me I II
o=c - c I
I
C0,Me
Me0
C0,Me
C0,Me
I
Ph3P0
+
I
N+CO,M~
M eOL%
0,Me
Me0
Isocyanates and isothiocyanates react in a similar way. Other reactions of the 1,3-dipole are described in Chapter 2, Section 7.
D. Miscellaneous.-It has been shown that allylmethylphenylphosphine does not undergo an allylic ~earrangement.~~ Racemisation, which is slower than racemisation of methylphenylpropylphosphine, must occur via pyramidal inversion. The rate of racemisation of t-butylmethylphenylphosphine 6o is similar to that of the two phosphines above, indicating that steric effects are not significant. Electron-withdrawing substituents in the para-position of the phenyl ring increase the rate of racemisation, indicating that the ( p - p ) ~conjugation affects the barrier to rotation. Similar electronic effects have been observed in a study of the rates of racemisation of diphosphines.61 Hydroxylamine has inadvertently been used as an oxidising agent 6 2 for tertiary phosphines in the preparation of the oximes (58). 58 6@
61
ea
E. Brunn and R. Huisgen, Angew. Chem. Internat. Edn., 1969, 8, 513. R. D. Baechler, W. B. Farnham, and K. Mislow, J. Amer. Chem. SOC.,1969,91, 5686. R. D. Baechler and K. Mislow, J. Amer. Chem. SOC.,1970, 92, 3090. J. B. Lambert, G. F. Jackson, and D. C. Mueller, J . Amer. Chem. SOC.,1970,92, 3093. M. D. Martz and L. D. Quin, J . Org. Chem., 1969, 34, 3195.
17
Phosphines and PhosphoniumlSalts
0
NOH
R
Hydrogenation of unsaturated phosphines (59) was foundto behossible over a palladium catalyst if the nickel(I1) complex was The addition of phosphorus trichloride to dilithiophenylphosphine 64 gave hexaphenyldecaphosphine (60).
Various lithiated tetra-, tri-, and di-phosphines are produced 66 from the addition of phenyl-lithium to ‘phenylphosphorus’ (PhP),. Tertiary phosphines and picric acid give, at room temperature, deeply coloured picrates believed to be covalent in character.s6 At lower temperatures yellow charge-transfer complexes are obtained. An equimolar mixture of triphenylphosphine and NN‘-bisbenzenesulphonyl-p-benzoquinonedi-imide (6 1) has been used as a dehydrating agent in the preparation of anhydrides, amides, and esters.67
0
N SO, P ti
PI1,P 3-
+
N SO,Ph
21iCOZH
-
+
Ph,PO
+
(RC0)20
1 lNSO,Ph
Peptide synthesis employing triphenylphosphine and 2,2’-dipyridyl disulphide in an oxidation-reduction condensation has been described.6s High reactivity with high optical purity is observed, which is rationalised by the intermediate formation of an acyloxyphosphonium salt (62) with predominant pentacovalent character, which reacts rapidly with the aminocomponent. as a* 6K 88
67
L. D. Quin, J. H. Somers, and R. H. Prince, J. Org. Chem., 1969, 34, 3700. M. Van Gheman and E. Wiber, U.S.P. 3,471,568. K. Issleib and F. Krech, Z . anorg. Chem., 1970, 372, 65. M. Beg, A. Arshad, and M. S. Siddiqui, Pakistan J. Sci. Ind. Res., 1969, 12, 19. M. Sprecher and D. Levy, Tetrahedron Letters, 1969, 4563. T. Mukaiyama, R. Matseuda, and M. Susuki, Tetrahedron Letters, 1970, 1901.
1s
Organophosphorus Chemistry
R R1 I I XNHCHCON HCHCOzY
0 II
--+
RCONHRl
+
Ph3P0
+
The chromatography of phosphines using various adsorbents has been reported.6B For the reaction of triphenylphosphine with TCNE and related compounds see Chapter 10, Section 2. PART 11: Phosphonium Salts 1 Preparation The quaternisation of triarylphosphines has been achieved using benzyne intermediate^.'^ The reaction of o-lithiofluoroaromatics with the phosphine at -75 "C leads to a mixture of betaines which can be protonated with fluorene. The same mixture is obtained from the lithiofluoroaromatics(63) and (64). H 3 c 0 ; i
(63)
\
H3C Ar,P
O9
70
+
ofAr3 -m +
CH,
M. C. Gonnet and A. Lamotte, Bull. SOC.chim. France, 1969, 2932. G . Wittig and H. Matzura, Annalen, 1970, 732, 97.
+
C,H, -PAr,
Phosphines and Phosphonium Salts
19
Tetra-arylphosphonium salts have been formed under Ullmann conditions by the reaction of triarylphosphines with iodobenzene in the presence of copper powder and cuprous iodide in DMF as Ph,P
+ PhI
'
~Ph,P ICuI~
~
3.
'
~
44%
Phosphorus pentachloride and phenylacetylene afforded tetrakisqchlorostyry1)phosphonium chloride (65) in low yield in the presence of iodine.' PCl,
+ PhC i CH
trace I z t
(PhCCI :CH),;
C1-
14% The nature of the phosphonium salt formed from the reaction of phosphorus pentachloride with vinylsilanes (66) depends upon the nature of (65)
x.73
PC15 f
+
R3Si.CH:CHX--+ XCH: C(SiR,) .PCI, PCIG
X = OMe, OEt
+
XCH:CH.PCl, PC1,-
X =BuS,PhCH, S
Quaternisation of triphenylphosphine with 1,3,2-dioxathiolan 2,2dioxide 74 gave the phosphonium salt (67).
Aminophosphonium salts (68) are obtained from the quaternisation of phosphines with N-brorn~amines.~~ R,NBr
+ R,P
+
___j
R,N-PR3 Br(68)
The synthesis of phosphonium salts containing the silyl group attached to phosphorus using silylcobalt tetracarbonyls (69) has been d e ~ c r i b e d . ~ ~ 71
73 74 76 76
A. V. Grib, Izuest. Akad. Nauk. S.S.S.R.Ser. khim., 1969, 195. Ya. P. Shaturskii, L. S. Moskalevskaya, G. K. Fedorova, and A. V. Kirsanov, Zhur. obshchei Khim., 1969, 39, 213.
N. V. Komarov, V. G. Rozinov, L. P. Vakhrushev, E. F. Grechkin, and N. F. Chernov, Izvest. Akad. Nauk S.S.S.R. Ser. khim., 1969, 729. D. A. Tomalia, U.S.P. 3,471,544. D. F. Clemens, W. Woodford, E. Dellinger, and 2. Tyndall, Inorg. Chem., 1969,8,998. J. F. Bald and A. G. MacDiarmid, J . Organometallic Chem., 1970, 22, C22.
Organophosphorus Chemistry No phosphonium salts are formed if electronegative groups are attached to either phosphorus or silicon. 20
Me,Si.Co(CO),
hexane + + PMe3 roomtemp. Me,Si.PMe,
Co(CO),-
(69)
Tri(cyclopropy1)phosphine and cyclopropyl bromide gave the tetracyclopropylphosphonium salt, which dissociates in solution.e Alkylated 1,4-diphosphoniacyclohexa-2,5-dienesalts (70) have been prepared from dialkyl-1-alkynylphosphines and hydrogen halide in acetic The yield of the/?-halogenovinylphosphine(71) by-product is decreased when hydrogen chloride is used instead of hydrogen bromide, indicating that the reaction mechanism is probably a series of acid-catalysed Michael additions, with halide ion competing with phosphine in the first step.
R2PC-CR1
+
HX
I ' I' I R,PC=CR1
X- --+
" 11R2PCH=CR1
X-
X
R,PC=CR'
R,PCH =CR'X
(71)
R'
-R
(70)
Tautomerism of (70)takes place in refluxing glacial acetic:acid a new organophosphorus heterocycle (72).
78
to give
The condensation of the cyclohexenediol (73) with triphenylphosphonium bromide 70 resulted in dehydration to yield the phosphonium salt (74). 77
?*
79
A. M. Aguiar, J. R. S. Irelan, G. W. Prejean, J. P. John, and G. J. Morrow, J . Org. Chem., 1969,34,2681. A. M. Aguiar, G. W. Prejean, J. R. S. Irelan, and G. J. Morrow, J. Org. Chem., 1969, 34, 4024. J. D. Surmatis, A. Walser, J. Gibas, and R. Thommen, J. Org. Chem., 1970, 35, 1053.
Phosphines and Phosphonium Salts
21
ofHzPP 4-
CH,OH H
O H
O
+
+
Ph,PH Br- --+
(74)
(73)
The preparation of a-chloro-substituted phosphonium salts from alkylidenephosphoranes is described in Chapter 8, Section 1B.
2 Reactions A. Alkaline Hydrolysis.-The alkaline hydrolysis of triphenylvinylphosphonium bromide with N NaOH gave (79, formed from rearrangement of the intermediate phosphorane (76). Another product, 1,Zbis(diphenylphosphiny1)ethane (77), is thought to arise from nucleophilic attack of the diphenylphosphinyl anion on unchanged salt, a scheme which is supported by the detection of styrene in the reaction mixture. Ph
c
Ph3P-CH = CH,
+
Ph -... I L P- CH =CH, *-
Ph
4 Lo
L
I Ph2P*CHPh* CH3
II
f---
0
Ph ,P*CHPhCHzII 0
(75) 1.
Ph,P*CHz*CH2.PPhz4
II
0
II
Ph,PCH=CH,
Ph2P=0
+
PhCH=CH,
0
Epimerisation has been found to proceed faster than hydrolysis in the base-catalysed cleavage of l-benzyl-1-phenyl-2,2,3,4,4-pentamethylphosphetanium bromides (78) (producing a mixture of phosphine oxides *l). In a related studys2 it has been shown that the ylides derived from cis- (78) and trans- (78) can also equilibrate. While pseudorotation undoubtedly occurs in the alkaline hydrolysis, it is difficult to see how ylide interconversion can proceed by such a process.
88
J. R. Shutt and S. Trippett, J. Chem. SOC.(C), 1969,2038. S. E. Cremer, R. J. Chorvat, and B. C. Trivedi, Chem. Comm., 1969, 769. J. Corfield, J. R. Shutt, and S. Trippett, Chem. Comm., 1969, 789.
2
22
Organophosphorus Chemistry Me
& '
(79a): (79b) = 9:l
Ph
"0
The hydrolysis of the optically active 2,2,3,3-tetramethylphosphetanium salt (80) proceeds with retention of configuration, the benzyl anion departing from the equatorial position in (81), or, after one pseudorotation, from the apical position of (82). The apparent anomaly in the hydrolysis of (78) has been explained by steric effects.s3 M eMee Me M e --+ M Me e e Me M e P -CH,Ph +\ Ph.
(80)
P---CH,Ph
HO"Ph (81)
M eMev Me M e P-CH,Ph / 'OH Ph
M Me e e Me M e / Ph
\*
(82)
The cis- and trans- isomers of the salt (83) do not interconvert under conditions where there is complete deuterium exchange.84 More vigorous conditions result in ring opening but there is still no crossover. Presumably pseudorotation is prevented because it would mean putting two t-butyl-like groups in apical positions (84), a high-energy situation.
(Ethoxy)methyl-@-naphthylphenylphosphonium nitrate and the corresponding ethylthio-hexachloroantimonate hydrolyse with inversion at phosphorus, indicating that a pseudorotation process does not occur in either case.24 The inversion of configuration observeds6 in the hydrolysis of t-butyl alkoxyphosphonium salts (85) is in contrast to the retention observed for 83
8G
K. E. DeBruin and K. Mislow, J. Amer. Chem. SOC.,1969, 91, 7393. S. E. Cremer and C. H. Chang, Chem. Comm., 1969, 1456. R. A. Lewis, K. Naumann, K. E. DeBruin, and K. Mislow, Chem. Comm., 1969, 1010.
Phosphines and Phosphonium Salts
23
other t-butyl phosphonium salts.*6 The difference is attributed to the nature of the leaving group, which in the former case is more electronegative than carbon. SbC1,P 11 Ph,+ -OH I --.P-OEt + HO-P-OEt : \ But 1 But Me Me
-OH +.
Ph O=Pc \ But Me
(85)
A careful study83 of the product ratios from the alkaline hydrolyses of the diastereoisomers of ethoxymenthoxymethylphenylphosphonium hexachloroantimonate (86) provides evidence for pseudorotation and leads to the view that there is steric control in product formation. The attack of hydroxide ion opposite menthoxy- is kinetically preferred to attack opposite the ethoxy-group.
SbC1,-
OEt SbC1,-
(88)
The preference of the four-memberedring for the apical-equatorial position is again shown 23 in the hydrolyses of the cis- and trans-ethoxyphosphonium salts (87), which proceed with retention of configuration. The reduction of 3-methyl-1-phenylphospholane-1-oxide(88) with hexachlorodisilane surprisingly proceeded with predominant inversion of config~ration,~~ even though the hydrolysis of the corresponding benzyl salts and reduction with phenylsilane proceeded with retention.88 Apparently when both the nucleophile and the departing anion are highly electronegative, the gain in stability by placing both these groups apical more than compensates for the induced strain when the five-membered ring is placed diequatorial. A kinetic study of the alkaline hydrolysis of ethylene-bis-phosphonium salts (89) has shown that a McEwen-type mechanism is operating.8s With 86
89
S. Trippett in ‘Organophosphorus Chemistry’ (Specialist Periodical Report), ed. S. Trippett, The Chemical Society, 1970, vol. 1, p. 28. W. Egan, G. Ghauviere, K. Mislow, R. T. Clark, and K. L. Marsi, Chem. Cornrn., 1970, 733. K. L. Marsi, J. Amer. Chern. SOC.,1970, 91, 4724. J. J. Brophy and M. J. Gallagher, Austral. J . Chern., 1969, 22, 1385.
Organophosphorus Chemistry
24
benzyl-substituted phosphorus atoms, loss of benzyl is competitive with fragmentation. The nature of the products obtained on hydrolysis of the salts (90) depends upon which reagent is in excess. Fragmentation can again be prevented if one uses a benzyl-substituted phosphorus atom.O0
+
+
+
Ph, P*CH2*CH2*PPh,+HOP(Ph,).CH2-CH2-PPh,
(89) +-~P(Ph,)--CH,
CH,c;Ph,,
W-
-
Ph3P :0
+
CH,: CH,
+
PPh,
0
II
PPh2 excess -OH
-OH _____, excess salt
f-------
(PPh, II
I P+E* Ph,
Ph2
0
(90)
When one isomer of the salt (91) was treated with aqueous base a mixture of oxides was produced. It would be interesting to see if the other isomer did the same and whether the isomeric salts could be interconverted in aqueous base.
The salts (92) have been hydrolysed by base in DMSO.sl When R = H, the P-phenyl bond is broken but when R = Ph, there is predominant cleavage of the cyclopropyl-C-P bond. This has been used as an experimental estimation of the pK,'s of diphenyl- and triphenyl-cyclopropene. PhwPh
-&I H X PPhz
phYph
II 0
R PPh,
ao*(32)
y= Ph3P=0 Ph
+
Ph
Ph Ptl
G . E. Driver and M. J. Gallagher, Chem. Comm., 1970, 150. M.A. Battiste and C. T.Sprouse, Tetrahedron Letters, 1969, 3165.
25
Phosphines and Phosphoniurn Salts
See Chapter 2 for the various topological representations of the stereochemistry of nucleophilic substitution reactions of phosphonium salts that have appeared. B. Additions to Vinylphosphonium Salts.-The use of adducts of vinylphosphonium salts and lY3-dipolesto yield further products by secondary steps has been Diphenyldiazomethane and triphenylvinytphosphonium bromide in methylene chloride gave a quantitative yield of (93). The ylide (94) formed by the action of base, gave a normal Wittig reaction. A high yield of 5,5-diphenyl-3H-pyrazoline(95) was obtained by reaction with sodium hydroxide. The action of heat gave the phosphonium salt (96), in contrast to the pyrolysis of the adduct from diazomethane and triphenylvinylphosphonium bromide, which gave pyrazoline hydrobromide (97) quantitatively.*
+
Ph3P-CH=CH,
4-
Ph3PCH=CH,
+ CH,N,
+
Ph Ph t C \ H , + PhzCNz 4 N\ ,CH-PPh, N
N3+ 3 A
I1
N
PPh,
>
HNz-. I
:+,;
HN'-
For the reaction of triphenylvinylphosphonium bromide with benzoin see Chapter 8, Section 1A. C. Miscellaneous.-In the presence of triethylamine, (prop-2-yny1)triphenylphosphonium bromide and benzoic acid form an adduct (98), presumably via the allenic salt, which can be used for the acylation of amine~.~~ O8
E. E. Schweizer, C. S. King, and R. A. Jones, Chem. Comm.,1970, 39. G. D. Appleyard and C. J. M. Stirling, J. Chem. SOC.(C), 1969, 1904.
* The structures of (93) and the adduct obtained from diazomethane and triphenylvinylphosphonium bromide have been revised (E. E. Schweizer, C. S. Kim, and R. A. Jones, Chem. Comm., 1970, 1584).
26
Organophosphorus Chemistry
+
Ph3P.CH,-CiCH
PhNHeCOR
PhCO H
[Ph,;.CH:CH:CH,]
+
PhNHz
-
Ph3P* CH, C :CH,
I OCOR
3.
+
(98)
Ph,P.CH,-CO.CH,
Allyltriphenylphosphoniumbromide rearranges on basic alumina to the prop- 1-enyl compound 94 which undergoes cathodic cleavageto propene and triphenylphosphine. The same rearrangement takes place thermally.96 In the same study, dehydrohalogenation of the salt (99) with one equivalent of base, or by heating it in diglyme, gave the allenylphosphonium salt (100) which was unreactive with methanol or t-butylthiol but with aniline gave (101). Treatment of (100) with more base yielded the cumulative ylide (102) (see Chapter 8). Et,N
t
>
Ph,P.CH,.CBr:CPhz (99)
+
Ph,P*CH,*C :CPh,
I
+
Ph,P.CH:C:CPha
Ph3P:C: C: CPh,
NHPh (101)
(102)
The 13C and l 8 0 isotope effects in the carbon dioxide formed in the acetolysis of triphenyl(carbobenzhydryloxymethy1)phosphonium bromide support a fragmentation process into benzhydryl carbonium ion, carbon dioxide, and methylenetriphenylphosphorane which is solvent-assisted.ss Other mechanisms operate for other salts when there is no likelihood of a stabilised carbonium ion being formed.
PART III: Phosphorins and Phosphoies 1 Phosphorins A. Preparation.-A new synthesis has been des~ribed.~'The phosphine oxide (103) produced by the dimerisation of the enone (104) with triethyl phosphite could not be reduced directly, but was converted into the dichloride and reduced with phenylsilane. Pyrolysis then gave (105). B4 s6
O6 s7
L. Horner, I. Ertel, H. D. Ruprecht, and 0. Belovsky, Chem. Ber., 1970, 103, 1582. K. W. Ratts and R. D. Partos, J. Amer. Chem. SOC.,1969, 91, 6112. S. Seltzer, A. Tsolis, and D. B. Denney, J. Amer. Chem. SOC.,1969, 91, 4236. G. Markl, D. E. Fischer, and H. Olbrich, Tetrahedron Letters, 1970, 645.
Phosphines and Phosphonium Salts
27
0 R-P,
,CH,OH CH,OH
+
reflux
(PhCH=CH)&=O
pyridiiie
R O FI ’ h R SeO, EtOH/R = PhCH,
CH,Ph Ph
I
Ph
J.
Ph
-A 0
(i) PCl, (ii) PhSiH,
Ph
Ph I CH,Ph
(EtO),P
Ph
Ph 04’\CH,Ph
Ph CH, Ph
(1 05)
A new class of phosphorus compound (106) has been prepared in a synthesis starting from one of the products of the photochemical cycloaddition of l-phenyl-3-phospholene oxide and dichloromaleimide.B8 (See Chapter 10, Section 1.) Azaphosphatriptycene (107) can be synthesised from tris(o-bromopheny1)amine using butyl-lithium followed by triphenyl phosphite.OO The slP spectrum of (107) is at very high field, + 80 ppm (CDCl,), using 35% HsPOl as standard.
gy 99
G. Mark1 and H. Schubert, Tetrahedron Letters, 1970, 1273. D. Hellwinkel and W. Schenk, Angew. Chem. Internat. Edn., 1969, 8, 987.
28 Organophosphorus Chemistry B. Structure.-The crystal structures of 1,l-dimethyl- loo and 1,l -dimethoxy-triphenylphosphorinlol have been determined and show that these compounds, like the phosphorins, owe their unusual stability to the presence of a delocalised aromatic ring.
C. Reactions.-Phosphorins have been oxidised with 2,4,6-triphenylphenoxyl radical to diaryloxyphosphorins (108).lo2In a similar reaction, the diphenylamino-radical gave the diphenylaminophosphorin (109). Both of these compounds can be oxidised, with lead@) benzoate or electrolytically, to the radical cation, in agreement with the presence of an aromatic nucleus. Ph O\ P ArO’
h
t---
phfiph
a
ph
PhZN -NPh,
,
Ph2N’
‘OAr
( 108)
Ar
4 ph
‘NPh,
(109) =
2,4,6-triphenylphenyl
2 Phospholes A review of the synthesis and reactions of phosphole derivatives has appeared.lo5 Quin has publishedlo4 a full account of his studies on l-methylphosphole confirming considerable delocalisation in the ring. A simple preparation of P-phenylphospholes, e.g. (1lo), has been reported lo5which consists of dehydrobromination of the adduct of a conjugated diene and dibromophenylphosphine with DBU in boiling benzene.
(1 10)
Further syntheses of dibenzophospholes (111) by o-hydrogen abstraction of tetraphenylphosphonium compounds with lithium bases are described.loB The low value of 16 kcal mol-1 for the inversion barrier of l-isopropyl-2methyl-5-phenylphosphole(112) has been attributed to ( 3 p - 2 ~ delocalisa)~ tion and aromaticity of the phosphole nucleus.1o7 Ph,P+ Br-
LiNEt,
>o-n ‘
P
’ Ph (111)
M e O F h CH(Me), (1 12)
J. J. Daly and G . Markl, Chem. Comm., 1969, 1057. lol U. Thewatt, Angew. Chem. Internat. Edn., 1969, 8, 769. loa K. Dimroth, A. Hettche, W. Stade, and F. W. Steuber, Angew. Chem. Internat. Edn., loo
1969, 8, 770.
A. N. Hughes and C. Srivanavjt, J. Heterocyclic Chem., 1970, 7 , 1. lo* L. D. Quin, J. G. Bryson, and C. G . Moreland, J . Amer. Chem. SOC.,1969, 91, 3308. lo6 M. F. Mathey, Compt. rend., 1969, 269, C , 1066. loo B. R. Ezzell and L. D. Freedman, J. Org. Chem., 1969,34, 1777. lo’ W. Egan, R. Tang, G. Zon, and K. Mislow, J. Amer. Chem. SOC.,1970,92, 1442. loS
2 Quinquecovalent Phosphorus Compounds BY S. TRIPPETT
1 Pseudorotation Additional topological 1-3 and non-topological representations of the processes of pseudorotation via a Berry mechanism have appeared. The preferred variation of a Balaban6 20-vertex graph is shown in the projections used by Mislow (l), by Cram (2), and by Nasielski (3). Each vertex 14
34
45
35
35
45
34
25
25
34
34
-
23
1'1
(3) a
*
K. E. DeBruin, K. Naumann, G. Zon, and K. Mislow, J . Amer. Chem. SOC.,1969,91, 703 1. D. Gorenstein and F. H. Westheimer, J. Amer. Chem. SOC., 1970, 92, 634. M. Gielen and J. Nasielski, Bull. SOC.chim. belges, 1969, 78,339. M. Gielen, C. Depasse-Delit, and J. Nasielski, Bull. SOC.chim. belges, 1969, 78,357. A. T. Balaban, D. Fgrcagiu, and R. Bani&, Rev. Roumaine Chim., 1966, 11, 1205.
30
Organophosphorus Chemistry
corresponds to one of the twenty possible trigonal bipyramids, designated by the groups occupying apical positions, and enantiorners are shown, for example, by 12 and 12. If a ring, which cannot span the diapical position, is present, (1) simplifies to the very useful (la), the ring being represented by substituents 1 and 2. The principles of pseudorotation are now being widely applied, particularly to phosphoranes postulated as intermediates in substitution processes at phosphorus. To avoid overlap, these are discussed in the subject chapters relating to the compounds being substituted. For n.m.r. investigations of stable quinquecovalent phosphorus compounds see Chapter 11.
2 2,2’-Biphenylylenephosphoranes Pseudorotation does not occur in the (8-dimethylamino-1-naphthy1)phosphorane (4) up to 120 “ C ;all the methyl groups are different including the two on nitrogen, both inversion at nitrogen and rotation around the
88 +
Me
Me
(7) S(31P) -t 82 p.p.m.
31
Quinquecovalent Phosphorus Compounds
naphthyl-nitrogen bond being sterically restricted.6 The activation energy of pseudorotation, AG* = 23.5 kcal mol-l, observed in the corresponding (8-methoxy-1-naphthy1)phosphorane raises the interesting possibility of obtaining these compounds in stable optically active forms. The hexaco-ordinate anion ( 5 ) was obtained as shown with either phosphonium ion or lithium as cation depending on the ratio of reactants. The corresponding anion from 1,s-dihydroxynaphthalene was also prepared. The dilithium salt of catechol with either phosphorus pentachloride or the chlorophosphorane ( 6 ) gave the anion (7), isolated as the bis(2,2'-biphenyly1ene)ammonium salt, which was stable in ethanol and in water. This anion had previously been obtained as the triethylammonium salt from phosphonitrilic chloride trimer and catechol in the presence of triethylamine, but was not positively identified at that time. 3 1,3,2-Dioxaphospholens While the phosphite (8; R1 = OMe) required heating at 100 "C for 30 h with butadienes in order to give the phosphoranes (9), the corresponding phosphonite (8; R1= Ph) reacted exothermically with butadienelO and with isoprene.ll This suggests that attack on the diene is an electrophilic process. Hydrolysis of the phosphoranes (9; R1 = Me or Ph, R2= Me) gave the 3-phospholens (10). @
Me
'
lo
l1
D. Hellwinkel and H. J. Wilfinger, Tetrahedron Letters, 1969, 3423. D. Hellwinkel and H. J. Wilfinger, Chem. Ber., 1970, 103, 1056. H. R. Allcock, J. Amer. Chem. SOC.,1964, 86, 2591. N. A. Razumova, F. V. Bagrov, and A. A. Petrov, Zhur. obshchei Khim., 1969, 39, 2369. N. A. Razumova, F. V. Bagrov, and A. A. Petrov, Zhur. obshchei Khim., 1969, 39, 2368. M. Wieber and W. R. HOOS, Tetrahedron Letters, 1969, 4693.
32
Organophosphorus Chemistry
The bromophosphorane (1 1; R1= Br), obtained from (8; R1= Br) and butadiene, with water gave l2 a compound to which the hydroxyphosphorane structure (12; R2= H) was assigned. This compound with diazomethane gave (12; R2 = Me) from which catechol was isolated after hydrolysis. The phosphorane (12; Ra= Me) was a highly crystalline substance, m.p. 112-1 14 "C, whereas the authentic material (9; R1= OMe, R2 = H) had b.p. 100-101 "C/2mm and was 'capable of crystallising on standing'. Hydrolysis of the fluorophosphorane (1 1 ; R1= F) @
OR2
(13)
with water at 70 "C gave the phosphinate (13) from which, after treatment with diazomethane and hydrolysis, catechol monomethyl ether was obtained.12 The different hydrolytic behaviour of the bromo- and fluorophosphoranes was ascribed to the different strengths of the phosphorushalogen bonds.
(15) I*
N. A, Razumova, Zh. L. Evtikhov, A. K. Voznesenskaya, and A. A. Petrov, Zhur. obshchei Khim., 1969, 39, 176.
33
Quinquecovalent Phosphorus Compounds
1,2-Naphthoquinone and triethyl phosphite gave l 3 the phosphorane (14), identical with that obtained from the phosphite (15) and diethyl peroxide. The products obtained l4 from acyl chlorides and the glyoxal-trimethyl phosphite adduct (16) have now been shown l6 to be the 0-acylated compounds (17). This contrasts with the C-acylation observed with the corresponding biacetyl adduct la (18; R1= Me). However, with the biacetyl adduct (18; R1= Et), attack on the carbon or oxygen depends l7 on the electrophile; with diethyl phosphorochloridite, the product (19) of attack on oxygen was obtained.
omo
3- R - C O - C l
-
R-CO-O*CH:CH-O-P(:O)(OMe), (17)
P ''
(OM43 (16)
-
(19)
Me
-
(EtO),P(: 0) CMe :CMe * 0 P(OEt),
74%
Me
(18)
R1 = Me, E\
R2.CO - CMe(C0 .Me) -0-I?(:
0) (OR1),
a-Chloro-/3-ketosulphides(21) have been obtained l8 from the exothermic reactions of the benzil-trimethyl phosphite adduct (20) with sulphenyl chlorides. These are neither radical nor carbene reactions and an ionic mechanism is suggested.
CY ' S-R -+Ph.CO.CPhCl*SR (21) 50-93%
l3
14,
l6 l6 l7
1*
D. B. Denney and D. H. Jones, J . Amer. Chem. Suc., 1969,91, 5821. F. Ramirez, S. L. Glaser, A. J. Bigler, and J. F. Pilot, J. Amer. Chem. Suc., 1969, 91, 496. F. Ramirez, S. L. Glaser, A. J. Bigler, and J. F. Pilot, J . Amer. Chem. Soc., 1969,91, 5966. F. Ramirez, S. B. Bhatia, A. J. Bigler, and C. P. Smith, J. Org. Chem., 1968, 33, 1192. I. P. Gozman, Zhur. ubshchei Khim., 1969, 39, 1954. D. N. Harpp and P. Mathiaparanam Tetrahedron Letters. 1970, 2089.
OrganophosphorusChemistry
34
For the photolytic reactions of the biacetyl-trimethyl phosphite adduct with ketones see Chapter 10. 4 1,3,2-Dioxaphospholans 1 :2-Adducts have been obtained from phosphonites and butyl glyoxalate lS and from phosphites and diethyl mesoxalate lS and (-)-menthy1 pyruvate.20 The adduct of the last with trimethyl phosphite gave (-)-2,3dimethyltartaric acid on hydrolysis; this was rationalised in terms of minimisation of non-bonded repulsions in the transition state for formation of the adduct. The phosphoranes (22), from ethyl ethylene phosphites and diethyl peroxide, decompose at or above room temperature l3 to give epoxides and triethyl phosphate. The formation of the cis-epoxide (24) from the transphosphorane (23) supports a mechanism involving a betaine intermediate.
Me :l>P(OEt) Me
[Fl:;+ Me
.__f 117°C
P(OEt),
Me
(EtO),PO
yo\+
Me €4'- MeP(OEt)3 -0 ' H
(23) Me
I
"b
Me
H
(24)
The observed relative rates of reaction of phosphites with diethyl peroxide (ethyl o-phenylene faster than saturated five-membered faster than acyclic and six-membered) suggest l3 that the phosphoranes are formed directly and not via intermediate phosphonium ethoxides. The increased ring-strain on going to tetrahedral intermediates would lead to the opposite order. The condensation of a-glycols with tris(dimethylamino)phosphine, to give phosphoramidites (25) or tetraoxyspirophosphoranes (26) depending on the ratio of reactants, has been extended 21 to a wide range of a-glycols including chiral molecules which give rise to interesting diastereoisomers. lo
A. N. Pudovik, I. V. Gur'yanova, and S. P. Perevezentseva, Zhur. obshcheiKhim., 1969, 39, 1532.
2o
21
M. Muroi, Y. Inouye, and M. Ohno, Bull. Chem. SOC.Japan, 1969,42,2948. H. Germa, M. Sanchez, R. Burgada, and R. Wolf, Bull. SOC.chim. France, 1970, 612.
Quinquecovalent Phosphorus Compounds
35
The spirophosphoranes (26) are stabilised 22 by methyl substituents; pinacol will displace either one or both of the ethylene glycol residues of (27) depending on the ratio of reactants. A 1 : 2 ratio of (27) and pinacol gave entirely the phosphorane (28). This phosphorane on heating with alcohols gave the phosphonate (29) instead of the expected phosphite, cf. (30) from (27).
-N Me,
R -f> :P
'y
(25)
+ PWMe,),
Y
H (26)
+ HO-CH2*CH2*OH
R O ) : [ (30)
H
H
+
2a
[;;P-o.co.R
H
-
H. Germa, M. Willson, and R. Burgada, Compt. rend., 1970, 270, C , 1426, 1474.
Organophosphorus Chemistry The trifluoroacetyl phosphite (3 1 ; R = CF,) reacted 23 twice as rapidly with butadiene as did the acetyl phosphite (31; R = Me), coniirming the increased reactivity of PI1[compounds with dienes with increasing electronacceptor ability of the substituents on phosphorus. 36
5 1,3,2-Oxazaphospholans Spirophosphoranes (32), (33), and (34) have been prepared as shown 24, 25 from a wide variety of 2-aminoalcohols, including (+) and (-)-ephedrine and L-alaninol, and the various stereochemical possibilities demonstrated by n.m.r. spectros~opy.~~, 26
+ P(NMe,),
+ R1
NHR2
6 1,2-Oxaphospholens Among new @-unsaturated ketones (35) used in the formation of 1 : l-adducts with tervalent phosphorus compounds (36) are methyl vinyl a3
ar *@
Zh. L. Evtikhov, N. A. Razumova, and A. A. Petrov, Zhur. obshchei Khim., 1969,39, 2367. M. Sanchez, L. Beslier, and R. Wolf, Bull. SOC.chim. France, 1969, 2778. J. Ferekh, J.-F. Brazier, A. Munoz, and R. Wolf, Compt. rend., 1970, 270, C, 865. M. Sanchez, L. Beslier, J. Roussel, and R. Wolf, Bull. SOC.chim. France, 1969, 3053.
37
Quinquecovalent Phosphorus Compounds
ketone,,* 27 ethyl benzylideneacetoacetate,2* 28 ethyl isopropylideneacetoacetate, isopropylideneacetylaceton e, and methyleneacetylacetone. Those with R6 = Rsare particularly useful as this reduces the number of isomers in the products. For a description of the n.m.r. spectra of these adducts see Chapter 11. (R10),PR2t3-,,)
+
R3* CO * CR4:CR'R'
Additional evidence has been presented2Bs30for the structures of the phosphoranes (38) and (39) obtained31 from the phenolic Mannich base (37) and tris(diethy1amino)phosphine.
+ P(NEt2), CH,.NEt,
(37)
+
+ kEt,
Me
(39) p7
A. K. Voznesenskaya, N. Razumova, and A. A. Petrov, Zhur. obshchei Khim., 1969, 39, 1033.
ao
81
B. A. Arbusov, E. N. Dianova, and V. S. Vinogradova, Izvest. Akad. Nauk S.S.S.R., Ser. khim., 1969, 1109. B. E. Ivanov, A. B. Ageeva, S . V. Pasmantuk, and R. R. Shagidullin, Izuest. Akad. Nauk S.S.S.R.,Ser. khim., 1969, 154. B. E. Ivanov, A. B. Ageeva, S . V. Pasmantuk, R. R. Shagidullin, S . G. Salikhov, and E. I. Loginova, Izvest. Akad. Nauk S.S.S.R., Ser. khim., 1969, 1757. B. E. Ivanov, A. B. Ageeva, and Yu. Yu. Samitov, Doklady Akad. Nauk S.S.S.R., 1967,174, 846.
38
Organophosphorus Chemistry
7 Miscellaneous Pentafluorobenzaldehyde and trimethyl phosphite in pentane at 0 "C gave32 a mixture of cis- and trans-2: l-adducts from which the pure cis-isomer (40) was isolated by crystallisation. Pseudorotation of this isomer was inhibited at - 130 "C. OMe H MeO. I .I
OMe f-f MeO. I ..
The reaction of diethyl peroxide with acyclic and cyclic phosphites to give pentaoxyphosphoranes has been extended33 to a wide variety of trisubstituted phosphines. The series Ph,P(OEt),,-,, (n = 1, 2, or 3) all gave the expected phosphoranes. Of the phosphines PhnPMe(3-n),that with n = 2 formed a stable phosphorane but the products when n = 0 and 1 appeared to be in equilibrium with the corresponding phosphonium ethoxides, e.g. PhPMe,(OEt),
Ph$Me,(OEt)
-
OEt
Of the aminophosphines Ph,P(NEt,),,-,, that with n = 2 gave a mixture of the phosphoranes (41) and (42) while those with n = 0 and 1 gave only the phosphine oxides. The cyclic aminophosphines (43; R = OEt and NMe,) formed unstable phosphoranes which rapidly decomposed to quadricovalent phosphorus compounds. PhzPNEt,
+ (EtO),
Ph,P(OEt), 3.Ph,P(OEt),(NEt,)
(41)
(42)
Oxadiazaphospholens (44) and (45) were formed 34 from triphenyl phosphite and the azo-compounds shown. An adduct analogous to (44) had previously been obtained 35 from trimethyl phosphite, while the structure of (45) confirmed the analogous formula put forward36 for the triphenyl phosphite-diethyl azodicarboxylate adduct. 3a
33
F. Ramirez, J. F. Pilot, C. P. Smith, S. B. Bhatia, and A. S. Gulati, J. Org. Chem., 1969,34, 3385. D. B. Denney, D. Z. Denney, B. C. Chang, and K. L. Marsi, J. Amer. Chem. SOC., 1969,91, 5243.
34
35
B. A. Arbusov, N. A. Polezhaeva, and V. S. Vinogradova, Izuest Akad. Nauk S.S.S.R., Ser. khim., 1968, 2525. B. A. Arbusov, N. A. Polezhaeva, V. S. Vinogradova, and Yu. Yu. Samitov, Izvest. Akad. Nauk S.S.S.R., Ser. khim., 1967, 1605. V . A. Ginsberg, M. N. Vasil'eva, S. S. Dubon, and A. Ya. Yakubovich, Zhur. obshchei Khim., 1960,30,2854.
39
Quinquecovalent Phosphorus Compounds
(44) rj(31P)+71.65 p.p.m.
OEt MeO,C.N:N.CO,Me+ (PhO),P
Ph,P
+
(Me0,C-N :),
___
-
Ph$.N(CO,Me).N.CO,Me
(46)
X
=
C0,Me
OAr 72%
Organophosphorus Chemistry
40
Quinquecovalent phosphorus compounds are implicated as intermediates in the trapping3' of the 1,3-dipolar species (46), formed from triphenylphosphine and dimethyl azodicarboxylate, with methyl propiolate and with 2,6-dimethylphenyl cyanate. The products from the decomposition of pentaphenylphosphorane in the presence of water, phenol, or t-butyl hydroperoxide are consistent 38 with a first step involving loss of a phenyl radical, e.g. Me,CO,H Ph5P
Dioxan
-I- -
' Ph,PO + PhOH + Ph,POPh + 86%
70%
Ph4$6Ph 53O/O 37 3g
llo/o
PhH 87%
+ Me,COH + Me,C:CH, 11%
43 '/o
+ PhH 5 0o/o
E. Brunn and R. Huisgen, Angew. Chem. Internat. Edn., 1969, 8, 513. G. A. Razuvaev, N. A. Osanova, and I. K. Grigor'eva, Izvest. Akad. Nauk S.S.S.R., Ser. khim., 1969, 2234.
3 Halogenophosphines and Related Compounds BY J. A. MILLER
1 Halogenophosphines
A. Preparation.-The preparation 1v of fluorophosphines by exchange of fluoride ion with chloride ion in solvents such as acetonitrilel and sulpholan has been reported. Another route to fluorophosphines, involving the reactions of carboxylic acid fluorides with phosphinous amides and phosphonous amides, has been used to prepare diphenylfluorophosphine (1) and difluorophenylphosphine (2). The monofluorophosphine is unstable and was characterised by n.m.r. and by its decomposition products [see B(iii), below]. Ph,PNHPr -II COP11
F
I’hCONI-IPr
___f
+
Ph,PF (1)
T 1
Ph,PNH r’r
Ph,PCI
I’h CO F PhP(r\;Me),
2 PhCONMe,
f PhPFz (2)
Aralkylhalogenophosphines may be prepared in good yield from aralkyl halides and phosphorus trihalides. These react at high temperatures to give aralkyldihalogenophosphines, which disproportionate on distillation in a current of nitrogen to yield monohalogenophosphines (3) and phosphorus t rihalides. I Ar-C-X
I
f
PX,
I (3)
a
a
C. Brown, M. Murray, and R. Schmutzler, J. Chem. SOC.(0,1970, 878. H. W. Roesky, Inorg. Nuclear Chem. Letters, 1969, 5, 891. Y. I. Baranov and S. V. Gorelenko, Zhur. obshchei Khim., 1969,39, 836.
42
Organophosphorus Chemistry
The synthesis of a variety of iododiphosphines has been reported. For example, phosphorus tri-iodide reacts with triphenylphosphine to give tetraiododiphosphine (4, R = I) (together with iodophosphonium salts); and dichlorophenylphosphine and cyclohexyldichlorophosphine give the diphosphines (4, R = Ph and R = C6Hll respectively) on treatment with iodide ion. When the reaction between dichlorophenylphosphine and iodide ion is carried out in benzene, the simple halogen-exchange product, di-iodophenylphosphine, was predominant. Ph3P
+
I I
1 I
+ RP-PR
PI3
f---
RPCI,
(4)
+
I-
I
R = Ph Benzene
PhP12
ButCl
+
PCI,
+
AICI,
___
+ ButPCI3 +
+
C1-
AICI,
Hydrolysis of the complex formed between t-butyl chloride, aluminium chloride, and phosphorus trichloride, failed to give t-butyl dichlorophosphine (5). This phosphine was prepared by desulphurisation of the corresponding sulphide (6j. Two other routes to t-butylphosphines have One involves the controlled displacement of chloride from dichloromethylphosphine by t-butylmagnesium chloride to produce the monochlorophosphine (7), which can then be converted to di-t-butylmethylphosphine under less stringent conditions. The second route starts from t-butyldichlorophosphine and involves the synthesis of the phosphinous amide (8), which is cleaved in the presence of hydrogen chloride to give (7). Treatment of (7) with sodium results in the formation of 1,2-dimethyl-l,2-di-t-butyldiphosphine (9), the n.m.r. spectrum of which indicates that only one diastereoisomer is present in solution. @
*
N. G. Feshchenko, Zh. K. Gorbatenko, and A. V. Kirsanov, Zhur. obshchei Khim., 1969,39, 2596. N. G. Feshchenko, T. V. Kovaleva, and A. V. Kirsanov, Zhur. obshchei Khim., 1969, 39, 2184. N. G. Feshchenko, E. A. Melnichuk, and A. V. Kirsanov, Zhur. obshchei Khim., 1969, 39, 2139. P. C. Crofts and D. M. Parker, J. Chem. Soc. (C), 1970, 332. W. Kuchen and G. Hagele, Chem. Ber., 1970,103, 2274. 0. J. Scherer and W. Gick, Chem. Ber., 1970, 103, 71.
Halogenophosphines and Related Compounds MePCl,
+
43
ButMgC1
k
20
y
Me P(13ut),
BU'M~C~
OC
Me--P
,But 'CI
(i) Et,NH (2 equiv.)
But P CI,
B. Reactions.-(i) Nucleophilic Attack at Phosphorus. Diary1 sulphides l o and ethers l1can be converted into phosphorus heterocycles (10, R1 = OH or alkyl; X = S or 0) of potential pharmaceutical interest, by reaction with aluminium chloride and phosphorus halides, followed by hydrolysis.
(R,
=
C1, alkyl)
The hydrolysis l2 of chlorodi-t-butylphosphine results in the formation of di-t-butylphosphine oxide, which is extremely stable to oxidation and to treatment with alkali. Aryldichlorophosphines are converted l3 to aryldialkylphosphine oxides (1 1) by successive treatment with iodide ion and an alkyl halide, followed by hydrolysis of the intermediates. ' 9
ArPCI,
I)
r-
(ii) RX
[ArR,PI,l
0 11 ---+ A r P R , H20
(50-7'573
(1 1)
A variety of anions will displace l4 chloride or bromide ion from difluorohalogenophosphines to give substituted difluorophosphines (1 2, Y = CN, CF,CO, or -NCO). An unusual reduction, of 2-bromocyclohexanol(l3) to lo
l1 la
l4
1. Granoth, A. Kalir, Z. Pelah, and E. D. Bergmann, Tetrahedron, 1969, 25, 3919. I. Granoth, A. Kalir, Z . Pelah, and E. D. Bergmann, Tetrahedron, 1970, 26, 813. A. P. Stewart and S. Trippett, J . Chem. SOC.(0,1970, 1263. N. G. Feshchenko, T. V. Kolaleva, and A. V. Kirsanov, Zhrn. obshchei Khim., 1969, 39, 2188. G . G . Flaskerud, K. E. Pullen, and J. M. Shreeve, Znorg. Chem., 1969, 8, 728.
Organophosphorus Chemistry
44
39%
36X
(13)
monobromocyclohexanol with phosphorus tribromide, is reported l5 to compete with the expected bromination to give 1,2-dibrornocyclohexanol. The first step in the complex reactions of tertiary phosphines with halogenophosphines is the formation 1 6 ~l7 of the phosphonium salts (14), and the factors which determine the further reactions of (14) to give R13P 4-
R2,PCl
PhzPCI
4
[R1,P-PR2,]+
-t PhXH
__j
CI-
Ph2P-Xph (1 7)
phosphoranes (1 5) or diphosphines (1 6) have been In general, simple trialkylphosphines give only adducts of type (14), but bulky trialkylphosphines and triarylphosphines give products containing phosphorusphosphorus bonds. Chlorodiphenylphosphine has been converted into the thio- and seleno-phosphines (17, X = S, and X = Se respectively). Phosphorus trichloride reacts l9 with hydroxylamine and hydrazine derivatives to give substituted chlorophosphines, which with sodium fluoride or antimony trifluoride give the corresponding substituted fluorophosphines (18, n = 1 or 2, X = OR or NR2). The reaction of methylhydrazine with bis(trifluoromethy1)iodophosphine gives 2o comparable amounts of (19)and (20). Treatment of halogenophosphines with imidates produces 21N-phosphinoimidates(21,R1= OEt or NMe, ;R2 = alkyl or aryl). l6 l7
*O
a1
G. Bellucci, F. Marioni, A. Marsili, P. L. Barili, and G. Berti, Chem. Comm., 1969, 1017. S. F. Spangenberg and H. H. Sisler, Znorg. Chem., 1969, 8, 1006. J. C. Summers and H. H. Sisler, Znorg. Chem., 1970, 9, 862. R. A. N. McLean, Znorg. Nuclear Chem. Letters, 1969, 5 , 745. A. E. Goya, M. D. Rosario, and J. W. Gilje, Inorg. Chem., 1969, 8, 725. L. K. Petersen and G. L. Wilson, Canad. J . Chem., 1969, 47, 4281. Y. Charbonnel, J. Barrans, and R. Burgada, Bull. SOC.chim. France, 1970, 1363.
-
Halogenophosphines and Related Compounds PCI,
+
RNHX
45
CI,P(NRX),-,
NaFl
(or SbF,)
F,P(NRX),(1 8)
+
,OMe
R1,PCI
4-
HN=C,
R1,P-N=C
___f
,OMe \
R2
RZ
(ii) Electrophilic Attack at Phosphorus. Conjugate addition reactions of a number of halogenophosphines have been reported. Chlorodialkylphosphines add 22 to 2-vinylpyridine to produce orange adducts, which decompose in the presence of proton donors, such as alcohols, to give 2-(~-dialkylphosphinyl)ethylpyridines(22). The quantitative formation 23 of a phosphorus-containingpolymer from chlorodiethylphosphine(23) and methyl acrylate can be similarly rationalised.
+ R1,PCl
+
I
[Et, PCH,CHCO,Me 1
I
aa
+
nCl-
V. S. Tsivunin, L. N . Krutskii, T. V. Zykova, and G. K. Kamai, Zhur. obshchei Khim., 1969,39,2666.
33
V. S. Tsivunin, S. K. Nurtdinov, R. R. Shagidullin, and G. K. Kamai, Zhur. obshchei Khim., 1969, 39, 1561.
46
Organophosphorus Chemistry
The formation 24 of (24) from chlorophosphines (25) and acrylamide has been explained on the basis of a conjugate addition by the phosphine, followed by phosphorane formation, since the rate of reaction of (25) decreases as R = alkyl, R = aryl or R = chlorine. Similar reactions of dichlorophosphines have previously been reported.25,26 -
c1*\C/NH2 ICH-p=O
R2
OCHS
reaction between toluene-p-sulphonyl azide and base and the diethyl ester of acetaldehyde-2-phosphonicacid, or, more simply, by diazotisation of the corresponding amine.80b On irradiation, they give the a-phosphonyl carbenes, which undergo typical hydrogen abstraction and insertion reactions; in addition, when R1= Ph, R2 = H, COPh, or C02Et, a phosphorus analogue of the Wolff rearrangement occurred, to give the phosphinic acid. F. Kasparek, Monatsh., 1969, 100, 2013. M. Regutz, H. Scherer, and W. Anschiitz, Tetrahedron Letters, 1970, 753. n o a M. Regitz and W. Anschutz, Annalen, 1969,730,194; D. Seyferth and R. S. Marmor, Tetrahedron Letters, 1970, 2493.
7*
70
112
Organophosphorus Chemistry
00-Dialkyl selenophosphonates (70) have been prepared by treatment of the chlorides with H2Sein the presence of triethylamine.sl
(70)
The preparation of an ATP analogue possessing methylene bridges between the phosphorus atoms has been achieveds2 by condensing the triphosphonic acid (7 1) [from Arbusov reaction on bis(chloromethy1)phosphonic acid 83] with adenosine using dicyclohexylcarbodi-imide (DCC). In the absence of nucleophiles, reaction of the acid (71) with DCC gave the methylene analogue of the cyclic trimetaphosphate ion. 0 II H203P-CH2-P-CHzP03H, I OH
HO, DCC
HzC’
I
HO-P,
C?
P
&O
‘YHz ,P=O
‘OH
(71)
B. Solvolyses of Phosphonic and Phosphinic Esters.-An intriguing neighbouring-group effect has been observed in the hydroxide-catalysed elimination of p-nitrophenol from the syn and anti isomers of oximinophenacyl p-nitrophenyl rnethylphosphonate (72a) and (72b).84 This proceeds loa and lo7 times faster than that from the corresponding ethyl ester, and also considerably faster than from phenacyl p-nitrophenyl methylphosphonate itself. Since nucleophilic participation by the oxime hydroxygroup is impossible in the anti isomer, the authors favour an intramolecular general-base catalysis. In the opinion of the Reporter, the high solvolytic rates seem abnormally large for such a mechanism-particularly in the case of the anti isomer, which would require a high degree of order in the transition state. Until the precise structure of the phosphorus-containing products are established, other mechanisms, including a rate-determining anti --f syn isomerisation for (72b), cannot be entirely excluded. The base hydrolysis of Sarin (73) is catalysed by cyclodextrin, the rates of the two enantiomers differing; that of the (It)(-), which forms the less-stable complex with the catalyst, is greater than that of the (S)(+),s5 As has been observed with similarly catalysed reactions, the rate constants do not vary linearly with cyclodextrin concentration but approach saturation values. The reaction of Sarin with anhydrous HC1 shows a thirdorder kinetic dependence.86 81
82
83 84
85 86
C. Krawieki, J. Michalski, R. A. Y. Jones, and A. R. Katritzky, Roczniki Chem., 1969, 43, 869. D. B. Trowbridge and G. L. Kenyon, J. Amer. Chem. SOC.,1970, 92, 2181. L. Maier, Helu. Chim. A d a , 1969, 52, 827. C. N. Lieske, J. W. Hovanec, and P. Blumbergs, Chem. Comm., 1969, 976. C. Van Hooidonk and J. C. A. E. Breebaart-Hansen, Rec. trav. chim.,1970, 89, 289. J. R. Bard, L. W. Daasch, and H. Klapper, J. Chem. and Eng. Data, 1970, 15, 134.
Quinquevalent Phosphorus Acids N-OH
0 ll Ph.C-CH,O-P --Me
II
113 HO-N
II
0
II Ph-C*CH20- P -Me
I
I
0 II
PriO-P-F
I Me (73)
The aqueous hydrolysis of a series of dialkyl phosphonates proceeds with P-0 cleavage, and the rates correlate with the Taft (T* values associated with the alkyl Fully esterified phosphonates 88 and phosphinates 89 appear, like many phosphate triesters, to undergo neutral solvolysis on the alkyl oxygen cleavage, and esters of secondary and tertiary alcohols follow an SN1 mechanism. Nucleophilic attack on dialkyl acylphosphonates occurs at carbon with expulsion of dialkyl phosphite anion.9o The attack of hydroxide ion on ethyl bis(dichlorornethy1)phosphinothioate (74) occurs on phosphorus, and is faster than the corresponding oxygen The anion of the phosphinothioate also undergoes rapid loss of chloride (unlike the corresponding phosphinate ion) giving the four-membered ring compound (75).92 Trichlorophos-T (76) rearranges readily under basic conditions to 2,2-dichlorovinyl dimethyl phosphate, and using 3H-labelled substrate it was found that the product contained 0-83 atommol-l of tritium in the vinyl group, supporting the proposed mechanism.93 The formation of 87
@O
B2
O3
V. E. Belskii, G. Z . Motygullin, V. N. Eliseenkov, and A. N. Pudovik, Izuest. Akad. Nauk S.S.S.R., Ser. khim., 1969, 1297. V. E. Belskii, G. Z. Motygullin, and 0. N. Grishina, Izuest. Akad. Nauk S.S.S.R., Ser. khim., 1969, 2813. V. E. Belskii, M. V. Efremova, I. M. Shermergorn, and A. N. Pudovik, Izuest. Akad. Nauk S.S.S.R., Ser. khim., 1969, 307. A. P. Pashukin, T. K. Gazizov, and A. N. Pudovik, Zhur. obshchei khim., 1970,40,28. V. E. Belskii, L. S. Andreeva, and I. M. Shermergorn, Izvest. Akad. Nauk S.S.S.R., Ser. khim., 1969, 2812. N. V. Ivasyvak and I. M. Shermergorn, Izuest. Akad. Nauk S.S.S.R., Ser. khim., 1969, 481. W. Dedek, H. Koch, G. Uhlenhut, and F. Broese, 2. Naturforsch., 1969, 24b, 663.
Organophosphorus Chemistry
114
(74)
F H 2 ,
-LcH;p:o-, -S-CH2
/p
S%H2/ P‘0(75)
0
Ql
tributyl phosphate from the related (77)with sodium hydroxide in butanol O4 doubtless follows a similar route involving an initial deacylation and finally an ester exchange reaction.
c1
/
0’
40 (Bu0)2P, CH(OAc)CCI,
BuOH base
,C-Cl \L Cl
’ (B u 0)3P=0
(77)
Hydrolysis of the cyclic anhydride (78) in H2l 8 0 indicates that attack proceeds with comparable facility on the carbonyl and phosphinyl groups.g6 The interpretation is, however, complicated owing to the fact that there was evidence that l 8 0 exchange could occur between the carboxyl and phosphinyl group in the product. P P P O 0’ ‘Et
0
u4
N. N. Mel’nikov, K. D. Shetsova-Shilovskaya, and I. L. Bogatyrev, Zhur. obshchei
85
Khim., 1969, 39, 2370. Y. Y . Efremov and V. K. Khairullin, Izvest. Akad. Nauk S.S.S.R., Ser. khim., 1969, 23 14.
115
Quinquevalent Phosphorus Acids
C. Reactions of Phosphonic and Phosphinic Acid Derivatives.-The optically active dithiopyrophosphonate (79) gave, as expected, optically active products with methoxide, but with lithium diethylamide a racemic
s
II EtO-P-0-P I Et
s I1
I
S -0Et
Et
Et NU
II
2EtO-P-NEt, I
Et
arnide was produced.ss I t was shown that the optically active amide did not racemise in the presence of the reagent, and it was therefore suggested that a pentacovalent intermediate was formed whose rate of breakdown was slow compared to the rate of pseudorotation. Using 2H-labelled substrate, it has been demonstrated that both isomers of l-rnethoxy-2,2,3,4,4-pentamethyl phosphetan-1-oxide (80) undergo methoxy-group exchanges with retention of configurati~n,~~ a result which was simply explained in terms of the preferred pseudorotational conformers of the pentacovalent intermediate.
Photochemical studies have been reported on various a-ketophosphonate esters (81). Irradiation of the n -+T* absorption region of the carbonyl group results in intermolecular hydrogen abstraction leading to pinacol formation when R1= Ar, R2 = Et, Pri, But, except with R1= Ph, R2 = Et, when the trioxan (82) is almost the sole The reason for the anomalous behaviour is not yet clear. With R1= Me, R2, R3= alkyl, intramolecular hydrogen abstraction from the alkoxy-group was and the products were rationalised in terms of the resulting biradical. Vinyl and acetylenic phosphonic acid derivatives behave as dienophiles, and in the reaction of [83; R2= C1 or (R10)2PO] with cyclopentadiene, 96
O7
9g 8s
M. Micolajczyk, J. Omelanczuk, and J. Michalski, Bull. Acad. polon. Sci., Sdr. Sci. chim., 1968, 16, 615. S. H. Cremer and B. C. Triveda, J . Amer. Chem. SOC.,1969, 91, 7200. K. Teranchi and H. Sakurai, Bull. Chem. SOC.Japan, 1970, 43, 883. Y. Ogata and H. Tomioka, J. Org. Chem., 1970, 35, 596.
116
Organophosphorus Chemistry
cyclohexadiene, or diazomethane, the expected adducts were formed.loO The dimer of the diethyl ester of buta-l,3-dienyl-l-phosphonic'acid has been shown to have the structure (84).lo1
OH .CR2R3
1 R1-C.>
o,
1
.'::pI! OCHR2R3 \
/
0
Y
P 0 CHR2R3 OH
&
R2R3
J
R'y ! 1 0 C € - I R 2 R 3
---+
0 II R1COCR2R3P 1 OCHR2R3 OH 0
The phosphinate ester (85) (from hypophosphorous acid and the diol) appears to exist in equilibrium with the cyclic form. Treatment of (85) with diazomethane gives 'the very labile phosphine (86),lo2 which reacts with 2-sulsulphur to give the known 5,5-dimethyl-l,3,2-dioxaphosphorinane phide. loo lol lo2
D. Seyferth and J. D. H. Paetsch, J . Org. Chem., 1969, 34, 1483. C. E. Griffin and W. M. Daniewski, J. Org. Chem., 1970, 35, 1691. E. E. Nifantev and L. M. Matveeva, Zhur. obshchei Khim., 1969, 39, 1555.
117
Quinquevalent Phosphorus Acids H.,
H 2
c-0 s
Me,C
/
\/
\
/\
C-0 H?.
P
H
Diphenyl phosphinothioic chloride and related active esters of the same acid have been investigated as potential reagents for radioactive labelling of imrnunoglob~lins.~~~
3 Miscellaneous An X-ray crystal study on 2-hydroxy-2-oxa-l,3,2,-dioxaphosphorinane (87; R = OH) shows that its structure, like other members of this ring system which have been determined, is a chair conformation in which the
(87)
angles around phosphorus are close to tetrahedral.lo4 N.m.r. studies indicate that in most cases, except where R = Ph, the P=O group preferentially adopts the equatorial position. There appears to be some conflicting evidence as to the extent of conformational mobility of this system. Variable-temperature n.m.r. studies and analysis of coupling coefficients on a wide range of derivatives have been interpreted in terms of reasonably facile conformational changes.lo5,lo6 However, other n.m.r. studies lo7 and some strong chemical evidence on the non-interconvertibility of (39) and (40)appear to rule out the possibility of interconversion between the two chair forms. It may turn out that this is critically dependent on the nature of the substituents. The conformations of the 1,3,2-dioxaphospholan derivatives (88) and dioxaphosphorinane (89) have been assigned on the basis of preparation from the phosphites and sulphur, in a reaction whose stereochemistry is R. A. Spence, J. M. Swan, and S. H. B. Wright, Austral. J. Chem., 1969, 22,2359. Mazhar-ul-Haque, C. N. Caughlan, and W. L. Moats, J. Org. Chem., 1970, 35, 1446. l o 6 R. S. Edmundsen and E. W. Mitchell, J . Chem. SOC. ( C ) , 1970, 1001. lo6 A. R. Katritzky, M. R. Nesbit, J. Michalski, Z. Tulimowski, and A. Zwierak, J. Chem. SOC.(B), 1970, 510. lo' M. Kainosho and A. Nakamura, Bull. Chem. SOC. Japan, 1969, 42, 1713. lo3 lo4
5
118
Organophosphorus Chemistry
established. l o 8 It appeared that trimethylamine dealkylates only isomer (89), in which the methyl group is cis to the phosphoryl P=S, presumably due to steric hindrance.log
ty?
Me
0 bMe
J>P&
(894
(88)
(89W
The absolute configuration of some optically active phosphonothioate esters has been deduced from the partial reduction of racemic dialkyl su1phoxides.ll0 Assignments on this basis were in agreement with those deduced from the lH n.m.r. spectrum of the a-phenylethylamine salts.111 Values of the Hammett (T have been measured from the dissociation constants of a series of m- andp-substituted benzoic acids (90; R = alkyl, OR, X = S or 0)112 and have been estimated from the laFshift 113 in the n.m.r. spectra of a series of 3-substituted fluorobenzenes. When R = phenyl, the two sets are in good agreement, but this is less so when R = alkoxy. Crystal structure determinations have been carried out on the phospholan (91),114 pyridoxal phosphate,l15 ATP,lls and OO-uridine-2’,3’cyclic-phosphorothioate.117
(90) lo9 111 112
11*
116 110
(91)
M. Micolajczyk, and H. M. Schiekel, Angew. Chem. Internat. Edn., 1969, 8, 511. M. Micolajczyk,Angew. Chem. Internat. Edn, 1969, 8, 511. M. Micolajczyk and M. Para, Chem. Comm., 1969, 1192. M. Micolajczyk, Chem. Comm., 1970, 654. E. N. Tvsetkov, D. I. Lobanov, L. A. Isosenkova, and M. I. Kabachnik, Zhur. obshchei Khim., 1969,39, 2177. H. Schindlbauer and W. Prikoszovich, Chem. Ber., 1969, 102, 2914. E. Alver and H. M. Kjnge, Acta Chem. Scand., 1969,23, 1101. T. Fujiwara and K. Tomita, Tetrahedron Letters, 1969, 2819. 0. Kennard, N. W. Isaacs, J. C. Coppola, A. J. Kirby, S. Warren, W. D. S. Motherwell, D. G. Waton, D. L. Wampler, D. H. Chenery, A. C. Larson, K. A. Kerr, and L. Riva de Sanseverino, Nature, 1970, 225, 333. W. Saenger and F. Eckstein, Angew. Chem. Internat. Edn., 1969, 8, 595.
7 Phosphates and Phosphonates of Biochemical Interest BY D. W. HUTCHINSON
1 Mono-, Oligo-, and Poly-nucleotides A. Mononuc1eotides.-A considerable number of papers has appeared during the past year on the synthesis of phosphate esters of nucleosides, particular attention being paid to those compounds which might have interesting pharmaceutical properties. The phosphorylation of unprotected nucleosides, mentioned in last year’s Report,l has continued to be developed. For example, phosphorus oxychloride has been used to prepare the 5’-phosphates of inosine 1-oxide,2 2-metho~yinosine,~ and other nucleoti Good yields of nucleoside 5’-phosphates have been obtained by treating unprotected nucleosides with pyrophosphoryl chloride (1) in phenolic solvents,6 and GMP* has been prepared from 2’,3’-O-isopropylidene guanosine using the same reagent.’ The phosphorylation of adenosine and uridine * by inorganic phosphates and polyphosphates has been cited as evidence for prebiotic phosphorylation. It has now been reported lo that sodium trimetaphosphate will phosphorylate nucleosides specifically in the 2’- and 3’-positions in aqueous alkali. An interesting method for the selective phosphorylation of nucleosides in the 5’-position involves the use of diethyl azodicarboxylate (2), triphenyl phosphine, and 1
2
D. W. Hutchinson in ‘Organophosphorus Chemistry,’ ed. S. Trippett (Specialist Periodical Report), The Chemical Society, London, 1970, Vol. 1, p. 145. A. Yamazaki, I. Kumashiro, and T. Takenishi, Chem. andPharm. Bull. (Japan), 1969,
17, 1128. A. Yamazaki, T. Saito, Y. Yamada, and I. Kumashiro, Chem. andPharm. Bull. (Japan), 1969, 17, 2581. 0 Fr. P., 1,531,156 (Chem. Abs., 1969, 71, 91,829). 5 M. Yoshikawa, T. Kato, and T. Takenishi, Bull. Chem. SOC.Japan, 1969, 42, 3505; G. Donaldson, M. R. Atkinson, and A. W. Murray, Biochim. Biophys. Acta, 1969,184, 655. 6 K. Imai, S. Fujii, K. Takanohashi, Y. Furukawa, T. Masuda, and M. Honjo, J . Org. Chem., 1969,34, 1547. 7 W. A. Gaines and D. F. Reinhold, Fr. P. 1,538,161 (Chem. Abs., 1969, 71, 70,902). a A. Schwartz and C. Ponnamperuma, Nature, 1968, 218, 443. 0 J. Rabinowitz, S. Chang, and C. Ponnamperuma, Nature, 1968, 218, 442. 10 A. W. Schwartz, Chem. Comm., 1969, 1393. 3
* The abbreviations used for biochemical compounds in this review may be found in the Instructions to Authors of the Journal of Biological Chemistry.
120
Organophosphorus Chemistry
dibenzyl hydrogen ph0sphate.l’ Tt has been suggested that the initial step in the reaction is the formation of a phosphonium complex from (2) and triphenyl phosphine. The large size of this complex favours reaction with the unprotected nucleoside at the relatively unhindered 5’-position to give (3). Interaction of (3) with dibenzyl hydrogen phosphate gives the dibenzyl ester of the nucleoside 5’-phosphate. C1,P(O)OP(O)CI,
+I
(1)
EtO,CN=NCO,Et
0
+ Ph,P
Q
(PhCH,O) ?PO I‘
HO
+
OPPh,
------+ Et0,CN-N=C-OEt I
/-
(3)
+ Et0,CN H-NCO,Et
H
Ph,PO
+
EtO,CNHNHCO,Et
Nucleosides can undergo transesterification with triethyl phosphite to give cyclic esters e.g. (4), which can be dealkylated with ammonia producing (5) or the 2’-(3’)-phosphite. Oxidation of (5) with hexachloracetone yields the corresponding cyclic phosphate. In this way, the phosphate esters of a number of nucleosides which contain unusual sugars have been obtained.12 This method has also been used to prepare the 2’,3’-cyclic phosphate of homouridine (6),13 a compound which was completely resistant to hydrolysis by pancreatic RNase. The 5’-phosphate of ( 6 ) which was prepared by treatment of 2-cyanoethyl phosphate with dicyclohexylcarbodi-imide (DCC) was completely resistant to attack by snake venom 5’-nucleotidases. l1 l2 l5
0. Mitsunobu, K. Kato, and J. Kimura, J , Amer. Chem. SOC.,1969, 91, 6510. A, Holf and F. Sorm, Coil. Czech. Chem. Comm., 1969, 34, 1929, 3383, and 3523; A. Holf, ibid., 1969, 34, 3510. A. Holf, Coil. Czech. Chem. Comm., 1970, 35, 81.
Phosphates and Phosphonates of Biochemical Interest
121 2-Cyanoethyl phosphate and DCC have been used to phosphorylate 4-thiouridine (7) l4 and L-arabinosyluracil (8),16 when the 2‘-, 3’-, and 5’monophosphates of (7) and (8) were obtained after treatment of the inter-
I
OEt
(4)
HO l4 l5
(8) M. Saneyoshi and F. Sawada, Chem. and Pharm. Bull. (Jnpan), 1969, 17, 181. J. R. Boisser, P. Lepine, J. De Rudder, and M. Privat de Garille, Fr. M. 5616 (Chenr. Abs., 1969, 71, 70,901).
122
Organophosphorus Chemistry
mediate 2-cyanoethyl nucleoside phosphodiesters with alkali. With 2’-deoxynucleosides,e.g. N(4)-alkyl analogues of 5-methyl-2’-deoxycytidine, selective phosphorylation of the 5‘-hydroxy-group has been reported.lG The 5’-phosphate of 7-deaza-adenosine(sparsomycin) (9) has been prepared from the 2’,3’-O-isopropylidene nucleoside by the 2-cyanoethyl phosphate/ DCC method,17 and was used to prepare dinucleoside 2‘ + 5‘- and 3’ 5’phosphates, with DCC as condensing agent. The 2-cyanoethyl ester of 2’,5’-di-O-( 1-ethoxyethyl)uridine 3’-phosphate (10) has been coupled with 2’-0-(l-ethoxyethyl)uridine to give a reasonable yield of the 3’ -+ 5’-linked dinucleoside phosphate.18 Apparently little or no reaction takes place between (10) and the free 3’-hydroxy-group of 2’-0-( 1-ethoxyethy1)uridine. --f
\
HO’
OH
(9)
HO, NCCH,CH,O
/
/d P
‘b
\
OCHMe
I
OEt
The 2-(a-pyridyl)ethyl group (ll), which has been used as a base-labile protecting group for phosphoric acids,lg is not labile under conditions required for the removal of 0- and N-acetyl groups; its removal requires rather more forcing conditions. This makes possible the selective removal of protecting groups from nucleotides, and (1 1) could be of importance in oligonucleotide synthesis.lgb The removal of (1 1) with methoxide or butoxide ion presumably follows a pathway analogous to that for the cleavage of 2-cyanoethyl groups. The synthesis of nucleotides containing modified sugar residues has continued to receive attention; for example, 5’-amino-5’-deoxy analogues of nucleotides [e.g. (12)] have been prepared.20 Hydrolysis of (12) by snake venom phosphodiesterase yields the phosphoramidate (1 3) which rapidly breaks down in the pH range 6.5-10 to orthophosphate and the amine (14). Cytidine 2’,3’-cyclic phosphate (15) can be converted into aracytidine 3’-phosphate (17; B = C , R = H) by treatment with trimethylsilyl l6 l7 l9
2o
T. Kulikowski, B. Zmudzka, and D. Shugar, Acta Biochim. Polon., 1969,16,201 (Chem. A h . , 1969, 71, 91,808). A. R. Hanze, U.S.P. 3,337,530 (Chem. Abs., 1969, 71, 61,724). G. W. Grams and R. L. Letsinger, J . Org. Chem., 1970, 35, 868. a W. Freist, R. Hebig, and F. Cramer, Chem. Ber., 1970, 103, 1032; W. Freist and F. Cramer, Angew. Chem. Internat. Edn., 1970, 9, 368. B. Jastorff and H. Hettler, Chem. Ber., 1969, 102, 4119.
Phosphates and Phosphonates of Biochemical Interest
Meo-J 0
I
+
123
ROLF’O- + 0
II
MeOH
OH
Ro
::
H) p i
yo>=
phosphodiesterase
HO
(H 0
’
HO
(12)
(13)
H
HSPOd
+
HO
(14)
chloride.21 An intermediate in this reaction is 0(2),2’-anhydrocytidine 3’-phosphate (16), which undergoes hydrolysis in either aqueous alkali or bicarbonate to yield (17; B = C, R = H). Trimethylsilylated uridine and adenosine 2’,3’-cyclic phosphates did not react under comparable conditions. An alternative method for the synthesis of (17; B = C, R = H) under mild conditions consists of treating the N(4)-dimethylaminomethylene or 5’-ON(4)-diacetyl derivative of (15) with a sulphonyl chloride or diphenyl phosphorochloridate at room temperature in anhydrous Hydrolysis of the protected (16) followed by removal of the protecting groups gave (17; B = C , R = H) in high yield. This method has been applied to the synthesis of polyarauridylic acid from polyrU.22bDinucleoside phosphates, e.g. (17; B = U, R = uridine-5’) have been prepared by the 2-cyanoethyl phosphate/DCC method using a protected anhydron ~ c l e o s i d e(17; . ~ ~ B = U, R = uridine-5’) was cleaved by both snake venom and spleen phosphodiesterases. The preparation and properties of nucleotides containing modified bases have been reviewed24 and several papers have appeared on the 21 22
23 24
J. Nagyvary, J . Amer. Chem. SOL‘.,1969, 91, 5409. J. Nagyvary and C. M. Tapiero, Tetrahedron Letters, 1969, 3481 ; ,7 R. G. Provenzale and J. Nagyvary, Biochemistry, 1970, 9, 1744. K. K. Ogilvie and D. Iwacha, Canad. J . Chem., 1970, 48, 862. F. Cramer, Accounts Chem. Res., 1969, 2 , 3 3 8 .
a
Organophosphorus Chemistry
124
NH
J
o‘pp+N
RNase T 6 GpN
where G > p 26
26 27 28 29
= guanosine
Snake venom + phospfiodiesterasc
G+pN
2’,3’-cycIic phosphate
M. Ikehara and S. Uesugi, Chem. and Pharm. BtdI. (Japan), 1969,17, 348; M. Ikehara, I. Tazawa, and T. Fukui, Chem. and Pharm. Bull. (Japan), 1969, 17, 1019. D. B. McCormick and G. E. Opar, J. Medicin. Chem., 1969, 12, 333. M. Ikehara and S. Uesugi, Tetrahedron Letters, 1970, 713. M. Tkehara, I. Tazawa, and T. Fukui, Biochemistry, 1969, 8, 736. A. Help and G. Kowollik, Coll. Czech. Chem. Comm., 1970,35, 1013.
Phosphates and Phosphonates of Biochemical Interest
125
Acrasin, the chemotactic agent which is responsible for aggregation of slime moulds, has been isolated and identified as adenosine 3’,5’-cyclic phosphate (19a).30 iso-Adenosine 3’,5’-cyclic phosphate (1 9b) has been prepared 31 by the action of butoxide on the 5’-(p-nitropheny1)ester 32 and its hormonal activity measured. The 3’-cyclic ester of 5’-deoxy-5’(dihydroxyphosphiny1methyl)adenosine (20) has been made 33 either by alkali 30 31
32
33
D. S. Barkley, Science, 1969, 165, 1133. G. Cehovic, I. Marcus, S. Vengadabady, and T. Posternak, Compt. rend. Sac. Phys. Hist. nat. Gentue, 1968, 3, 135 (Chem. A h . , 1969, 71, 81,688). R. K. Borden and N. Smith, J . Org. Chem., 1966, 31, 3247. G. H. Jones and J. G. Moffatt, U.S.P. 3,446,793 (Chem. Abs., 1969, 71, 70,903).
126
Organophosphorus Chemistry
treatment of a monoester 32 or by cyclisation with DCC;34it has similar pharmacological activity to (19a), but is less susceptible to hydrolysis. From a study of the equilibrium of the adenyl cyclase reaction it has been calculated 35 that the free energy of hydrolysis of (19a) is - 11-9kcal mol-1 at pH 7 and 25 "C,i.e. about 3 kcal mol-1 greater than the free energy of hydrolysis of ATP under comparable condition^.^^ The enthalpy of hydrolysis of (19a) to AMP has now been determined calorimetrically 37 as - 14.1 kcal mol-1 and hence it appears that the entropic contribution to the hydrolysis must be small. The enthalpy of hydrolysis of (19c) is smaller than that of (19a) but there is still a considerable release of energy during hydrolysis. The configuration at the 3'-position in (19a) was established by the degradation of the 0-methylated nucleotide with liquid hydrogen fluoride, the product being 2-O-rnethylribo~e.~~ Fluoride ion is a strong nucleophile for phosphoryl centres and hydrogen fluoride is a highly specific dephosphorylating agent for n u c l e ~ t i d e s .The ~ ~ reaction is dependent on temperature, time, and acid strength, and conditions have been described for the (a) R
=
adenosine
degradation of nucleotides to nucleosides or bases. Extended exposure to hydrogen fluoride appears to cause no deamination of adenine, guanine, or cytosine, and base analysis of RNA can be carried out with this reagent. From a study of n.m.r. data on the binding of cytidine 3'-phosphate to pancreatic RNase together with X-ray evidence concerning the structure 34
36
38
37
38 39
M. Smith, G. I. Drummond, and H. G . Khorana, J. Amer. Chem. SOC.,1961,83, 698. P. Greengard, 0. Hayaishi, and S. P. Colowick, Fed. Proc., 1969, 28, 467. R. A. Alberty, J. Chem. Educ., 1969,46, 713; R. A. Alberty, J. Biol. Chem., 1969, 244, 3290. P. Greengard, S. A. Rudolph, and J. M. Sturtevant, J . Biol. Chem., 1969, 244, 4798. D. Lipkin, W. H. Cook, and R. Markham, J . Amer. Chem. SOC.,1959, 81, 6198. D. Lipkin, B. E. Phillips, and J. W. Abrell, J . Org. Chem., 1969, 34, 1539.
Phosphates and Phosphonates 0f Biochemical Interest
127 of the enzyme, it has been suggested 40 that a ‘linear’ mechanism is more likely for RNase-catalysed hydrolysis reactions than a mechanism which involves the Pseudorotation Of a pentacovalent intermediate. Furthermore, it has been shown that during the enzymic hydrolysis of uridine 2’,3’-0cyclophosphorothioate,41a sulphur is not lost to the solvent.*lb This latter observation implies that pseudorotation of an intermediate pentacovalent adduct does not occur during the hydrolysis reaction. The rate of RNasecatalysed hydrolysis of uridine 2’,3’-cyclic phosphonate (20) is much lower than that for the hydrolysis of the corresponding phosphate. If pseudorotation occurs during the hydrolysis, one form of the pentacovalent intermediate requires a relatively electropositive methylene group to be in the apical position.4Z This would not be a favoured process43 and hence should have an adverse effect on the rate of hydrolysis. Kinetic measurement of the pancreatic RNase-catalysed hydrolysis of uridine 2‘,3‘-cyclic phosphate to uridine 3’-phosphate indicates that the mechanism is very similar to that for cytidine 2’,3’-cyclic phosphate.44 The degree of ionisation of the cytidine ring seems to be relatively unimportant in the latter case and the same ionisable groups on the enzyme are probably involved in both reactions. Temperature-jump studies show that two processes are involved in the interaction of pancreatic RNase and uridine 3’-ph0sphate,~~ an initial association of the enzyme and the nucleotide being followed by an isomerisation of the enzyme-nucleotide complex. At least three ionisable groups on the enzyme are involved and these results have been correlated with the known three-dimensional structure of the enzyme. Formycin (21) is an analogue of adenosine and its triphosphate can replace ATP in RNA polymerase Copolymers containing (21) can be prepared, e.g. poly(F-C) and poly(F-U), and these are susceptible to hydrolysis by pancreatic RNase giving rise to FpCp and FpUp respectively. These dinucleotides undergo further hydrolysis by the enzyme to the mononucleotides, The cyclic 2’,3’-phosphate of (21) is also unusual in undergoing enzymic hydrolysis by pancreatic R N ~ s ~ .It~ is’ difficult to see why phosphate esters of (21) are hydrolysed by this enzyme as the size and shape of the heterocyclic base are unlike those of a pyrimidine. How40
4l 42
43
44
a5 48
47
G . C. K. Roberts, E. A. Dennis, D. H. Meadows, J. S. Cohen, and 0.Jardetzky, Proc. Nnt. Acad. Sci. U.S.A., 1969, 62, 1151. W. Saenger and F. Eckstein, Angew. Chem. Internat. Edn, 1969, 8, 595; F. Eckstein, F.E.B.S. Letters, 1968, 2, 85. M.R. Harris, D. A. Usher, H. P. Albrecht, G, H. Jones, and J. G . Moffatt, Pruc. Nut. Acad. Sci. U.S.A., 1969, 63,246. F. H. Westheimer, Accounts Chem. Res., 1968, 1, 70; D. A. Usher, Proc. Nut. Acad. Sci. U.S.A., 1969, 62, 661. E. J. del Rosario and G. G. Hammes, Biochemistry, 1969, 8, 1884. G . G. Hamrnes and F. G. Walz jun., J . Amer. Chem. SOC.,1969, 91, 7179. M. Ikehara, K. Murao, F. Harada, and S. Nishimura, Biochim. Biophys. Acta, 1968, 355, 82; D. C . Ward, A. Cerami, E. Reich, G. Acs, and L. Altwerger, J. Biol. Chem., 1969, 244, 3243. M. Ikehara, K. Murao, and S. Nishimura, Biochim. Biophys. Acta, 1969, 182, 276.
128
Organophosphorus Chemistry
ever, the base does contain an ionisable NH group which is not present in either adenine or guanine and this may have a catalytic effect on the hydrolysis reaction. B. Nucleoside Po1yphosphates.-The synthesis of o~-~~P-Iabelled nucleoside di- and tri-phosphates has been 49 The most efficient method 49 consists of treating the S2P-labelledmonophosphates 6o with 2-cyanoethyl phosphorimidazolidate (22) or 2-cyanoethyl pyrophosphorimidazolidate (23) followed by base. The imidazolidates (22) and (23) can be obtained from the reaction between NN-carbonyldi-imidazole (24) and 0
+ N C ( C H , ) , OII P - N ~ N I \ / 0€1 HO
OH
0 0
NC (CH, ) ,O -PO P ''0 HO OH
HO
O€I
HO$O:2 0 0 !oyo?,B
I I OH OH HO
0 ll
O€I
8 II
N~N-P-O-P-OCH,CH,CN L f OH I 0I € 1
(23)
N~N-CO-N%
u
L f
(24)
2-cyanoethyl-phosphate or -pyrophosphate. It is claimed that the use of (22) and (23) is preferable to the use of (24) in con,junction with ortho- or pyro-phosphate.61 The latter method has been widely used in the past for 48 48
61
R. H. Symons, Biochim. Biophys. Acta, 1969, 190, 548. R. H. Symons, Biochim. Biophys. Acta, 1970, 209, 296. R. H. Symons, Biochem. Biophys. Res. Comm., 1966,24,872; R. H. Symons, Biochim. Biophys. Acta, 1968, 155. 609. D. E. Hoard and D. G. Ott, J . Amer. Chem. Soc., 1965, 87, 1785; D. G. Ott, V. N. Kerr, E. Hansbury, and F. N. Hayes, Analyt. Biochem., 1967, 21, 469.
Phosphates and Phosphonates of Biochemical Interest
129 the synthesis of nucleoside polyphosphates, e.g. 6-mercapto-9-fl-~-ribofuranosylpurine 5’4ripho~phate.~~ Adenosine 5’-bis(dihydroxyphosphinylmethy1)phosphinate (25) has been prepared 5 3 by treating 2’,3’-O-isopropylidene adenosine with the trimetaphosphate analogue of bis(dihydroxyphosphinylmethy1)phosphinic Since (25) contains no labile P-0-P bonds it would be interesting to investigate the inhibiting properties of this compound in enzymatic systems which require ATP as cofactor. Guanosine 5’-phosphohypophosphate (26)
HiC,
P
,CH,
/ \ 0 OH
0 0 0 II I1 II ROP-0-P-P-OH
I
HO
where R
I I HO O€I (26) =
guanosine
0
0
0
OH OH OH HO
OH
(25)
which is obtained from the exchange reaction between P1-guanosine-5’, P2-diphenyl pyrophosphate, and hypophosphoric is a strong competitive inhibitor of protein biosynthesis when used in place of GTP ;5s it permits the binding of fMet-tRNA to ribosomes, but is less effective than GTP. The determination of the three-dimensional structure of ATP as its hydrated sodium salt shows that two crystallographically independent forms of ATP are present, differing only in the orientation of the 5’-oxygen with respect to the ribose ring.57 In both forms the polyphosphate chain is folded back towards the purine base, in contrast to inorganic tripolyphosphate which exists in an extended form in the crystalline state. There also appears to be a difference between the conformations of the poly62
63 64 65 56
A. J. Murphy, J. A. Duke, and L. Stowring, Arch. Biochem. Biophys., 1970, 137, 297. D. B, Trowbridge and G . L. Kenyon, J . Amer. Chem. SOC.,1970,92, 2181. L. Maier, Helv. Chim. Acta, 1969, 52, 827. P. Remy, G. Dirheimer, and J. P. Ebel, Biochim. Biophys. Acta, 1967, 136, 99. P. Remy, M. L. Engel, G . Dirheimer, J. P. Ebel, and M. Revel, J . Mol. Biol., 1970, 48, 173.
57
0. Kennard, N. W. Isaacs, J. C. Coppola, A. J. Kirby, S. G . Warren, W. D . S. Motherwell, D. G . Watson, D. L. Wampler, D. H. Chenery, A. C. Larson, K. A. Kerr, and L. Riva di Sanseverino, Nature, 1970, 225, 333.
130
Organophosphorus Chemistry
phosphate chains in ATP and inorganic tripolyphosphate in solution 6 8 as the pH dependence of the spin-spin coupling in the 31Pn.m.r. spectra of ATP and ADP is different from that for linear tripolyph~sphate.~~
C. Oligo- and Poly-nuc1eotides.-The
most monumental feat in the field of polynucleotide chemistry during the past year has been the synthesis 6o of a gene for the principal alanine t-RNA in yeast. In essence, the synthesis consists of the exploitation of the ability of chemically synthesised oligodeoxynucleotides to form specific base-paired dimers and the linking of these dimers with T4 polynucleotide ligase. A total of seventeen segments, varying in chain length from penta- to icosa-nucleotides, were synthesised ZO 19 18 17 I6 I5 14 I3 I2 I I 10 9 8 7 6 5 4 3 2 1 G A U V C C G G A C U C G U C C A C C A -(4)I (1) -'c- T-A-A- G- G-C-C' 'T-G-AG- C- A- G-G-T-G-G-T'
1 1 1 1 1 1 T-1 C1 -G 1 -T,1 ,C1 -C-1 1 1 1 1
IC- C- G- G-A-F-
(3')RlOO (5') DEOXY
(3') DEOXY
50 49 48 47 4 6 45 44 4 3 42 41 40 39 38 37 36 35 34 33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17
Me2 - G C V C C C U U
Me
l
G
C
l
Y
G
G
G
A
G
A
G
H2 U C
V
C
C
G
G
T
Y
C
G
A
U
U
(35RRlBO
77 76 75 74 73 12 71 70 69 68 67 66 65 6 4 63 62 61 60 59 9 57 56 55 54 53 52 51 M 49 48 47 46
k?
Me
G G
G C G U G U G G 1 (4-)
Ic-C-C-G-C-A-C-A-C-C-G-c
C
G C G U A G U C ,-1 2 )(-, G-C-A-T-C-A-G-C-C--A
H2 G G V A
G C
M-2 G C G C
V
C
C-
(51) MOXY
T-C-G-C-G-C-G-A-G-G-
I I I I I I I T-G-G-C-G-C-G-T-A-G I I I I I I I l l l T-C-G-G-T-A-G-C-G-C t l l l l l l l l l
(35 DEOXY
G-G-G-C-G-T-G
-(l5)-
-(13)
(2hRlBO
y ( I Q > - a
n (I-
77 76 15 14 7 3 72 71 70 69 68 67 66 65 64 63 €2 61 80 59 58 57 56 55 54 %3 52 3 x) 49 48 47 46 Me
G G . -r
c-
G C G U G U G G C G C G V A (I41 G- C-A-TC- C- G- C- A- C-A- G-C-G-C
-
H2 H2 M.2 G U C G G U A G C G C G C U C (12') 1 (10') C- A-G-C-CA-T-C G- C- G-C-G-A-G-G-
-,
1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1
G-G-G-C-G-T-G I ( I 5 ) -
T-G-G-CG-C-G-T-AL-----(13)AL----(II)----J
G 7-C-G-G-T-A-G-C-
G-C-
C-
(3'1RleO
(5') M O X Y
(3) DEOXY
Totalplanfor the synthesis of a yeast alanine tRNA gene. The chemically synthesised segments are in brackets, the serial number of the segment being shown within the brackets. A total of seventeen segments (including 10 and 12) varying in chain length from penta- to icosa-nucleotides were synthesised. The assumption was made that the rare bases present in the tRNA arise by subsequent modification of the four standard bases used by the transcribing enzyme. Thus inosine is formed by deamination of adenosine and so comes from an A . T base-pair in D N A (Reproduced by permission from Nature, 1970, 227, 27) 68
65
eo
M. Ellenberger, L. Brehamet, M. Villeimin, and F. Toma, F.E.B.S. Letters, 1970, 8, 125. M. M. Crutchfield, C. F. Callis, R. R. Irani, and G. C. Roth, Znurg. Chem., 1962, 1, 813. K. L. Argarwal, H. Buchi, M. H. Caruthers, N. Gupta, H. G . Khorana, K. Kleppe, A. Kumar, E. Ohtsuka, U. L. Rajbhandary, J. H. van de Sande, V. Sgaramella, H. Weber, and T. Yamada, Nature, 1970, 227, 27.
Phosphates and Phosphonates of Biochemical Interest
131
by the general methods developed by Khorana's school in recent years.61 To simplify the task it was assumed that the atypical bases in the t-RNA arose by subsequent modification of the four standard bases used by the transcribing enzyme. Initial experiments suggest that DNA polymerase may be able to replicate the gene in the presence of suitable primers and that transcription of the appropriate strand to produce the t-RNAmay bepossible. Three deoxyribododecanucleotides of defined sequence have been synthesiseds2 by a method which doubled the chain length of the oligonucleotides at each condensation step. In this way, the products and reactants differ sufficiently in molecular weight to be separated by Sephadex gel filtration with appropriate exclusion limits. An advantage of this method of separation is that it is rapid, and the product emerges from the chromatographic column before the reactants. The oligonucleotides are related to the DNA sequence of the gene corresponding to bovine insulin Chain A. 4-Chloro-2-nitrophenol has been used 63 as a base-labile protecting group for phosphate groups in the synthesis of homodeoxyribo-oligonucleotides. The conditions required for its removal ( 2 sodium ~ hydroxide 100 "C/ 15 min), however, cause some deamination of adenine residues and four new base-labile protecting groups have been developed (27; R1 = C,H5), (27; R1 = 4-Me0.C,H4), (27; R1= PhCH,), and (2Q6* (27) and (28) are removed rapidly by 2~ sodium hydroxide at room temperature. Protecting groups (e.g. substituted acetals) which can be preferentially removed under carefully defined conditions have been successfully used in the synthesis of oligoribonucleotides.6s 0
II
ROP-OH I OH
(27) R = R1C0CH2CH2(28) R = PhCH=Nisoamyl nitrite
OBz
HO
where CBz Ba
64
65
OBz
7 O€I
=
N(4)-benzoylcytosine
H. G. Khorana, Pure Appl. Chem., 1968,17,313; Biochent. J., 1968,109, 709. S . A. Narang and S. K. Dheer, Biochemisiry, 1969, 8, 3443. S. A. Narang, 0. S. Bhanot, J . Goodchild, and R. H. Wightman, Chem. Comm., 1970, 91. S. A. Narang, 0. S. Bhanot, J. Goodchild, J. Michniewiez, R. Wightman, and S. K. Dheer, Chem. Comm.. 1970. 516. B. E. Griffin and C. B. Reese, Tetrahedron, 1969, 25, 4057.
132
Organophosphorus Chemistry
Aromatic phosphoramidates of protected nucleosides (29) can be degraded to the corresponding phosphates (30) by isoamyl nitrite without affecting other protecting groups,66 and this reaction has been used to prepare oligoribonucleotides of defined sequence.67 The 3’-end of an oligoribonucleotide can be protected during synthesis by a 2’,3’-cyclic phosphate group.6s Pancreatic RNase will cleave the cyclic phosphate to liberate the 3’-phosphate and phosphoryl migration can be prevented by acetylation of the 2’-hydroxy-group. Phosphorofluoridates can act as phosphorylating agents in the presence of strong base and have been used in a highly specific synthesis of oligodeoxyribonucleotides.70 No pyrophosphate formation occurs under these conditions, and dinucleoside phosphates can be obtained in high yield. This method should be particularly applicable to the synthesis of acidlabile phosphate esters. 3-4’(5’)-Imidazolyl propanoic acid (3 1) will catalyse the polymerisation of deoxyribonucleoside 5’-phosphates to give oligonucleotides,71 and although the mechanism of this reaction has not been studied it is probable
)P=O F
Merrifield resin
that nucleoside 5’-phosphorimidazolidates are intermediates. Adenosine and deoxyadenosine 5’-phosphorimidazolidates will participate in the template-directed synthesis of oligomers in the presence of a sterically ge
67
6g ‘O
E. Ohtsuka, K. Murao, M. Ubasawa, and M. Ikehara, J. Amer. Chem. SOC.,1970, 92, 3441. E. Ohtsuka, K. Murao, N. Ubasawa, and M. Ikehara, J. Amer. Chem. SOC.,1970, 92, 3445. T. Nejlson, Chem. Comm., 1969, 1139. R. Wittmann, Chem. Ber., 1963, 96, 771. R. G. von Tigerstrom and M. Smith, Science, 1970, 167, 1266. 0. Pongs and P. 0. P. Ts’o, Biochem. Biophys. Res. Comm., 1969, 36, 475,
Phosphates and Phosphonates of Biochemical Interest
133
suitable nucleoside Thus, a-adenosine and ara-adenosine are less effective substrates than /I-adenosine. Commercially available ‘Merrifield’ resin has been modified into a form which contains acyl chloride groups.73 This resin will esterify the 5‘hydroxy-group of thymidine which can then serve as a starting material for the synthesis of oligothymidylic acids. In the final step, the product can be removed from the resin by treatment with ammonia. The enzymic synthesis of a large number of oligo- and poly-nucleotides has been reported in the past year. Among the enzymes used have been ribonucleases (e.g. T, or N1),74-7a polynucleotide phosph~rylase,~~-~* and terminal nucleotidyl tran~ferase.~~f 86 The successful polymerisation of the 5’-pyrophosphates of atypical nucleosides can depend on the source of the polynucleotide phosphorylase 83 or on the substitution of manganese for magnesium in the medium.84 The ‘lag phase’ which has sometimes been observed 8 7 in the polymerisation of ADP with polynucleotide phosphorylase has been found to be of universal occurrence once care has been taken to remove contaminating oligo- and poly-nucleotides from the enzyme.aa It has been suggested that the lag is due to the enzyme having a more favourable conformation when it is bound to a primer, and hence the rate of enzymic synthesis is more rapid in the presence of a primer than in its absence. Venom exonuclease can be used to determine the chain length and the termini of oligonucleotides which have a 3’-phosphate group.89 Relatively large amounts of enzyme must be used and the reaction is slow, as the presence of a negatively charged group in the 3’-position of the oligomer has an adverse effect.g0 72 73 74 75
76
77
78
7g
83
84 85 86
89
H. Schneider-Bernloehr, R. Lohrmann, J. Sulston, L. E. Orgel, and H. Todd Miles, J . Mol. Biol., 1970, 47, 257. T. Kusama and H. Hayatsu, Chem. and Pharm. Bull. (Japan), 1970, 18, 319. J. Smrt, Coll. Czech. Chem. Comm., 1969, 34, 1702. T. Koike, T. Uchida, and F. Egami, Biochim. Biophys. Acta, 1969, 190, 257; S. Irie, T. Uchida, and F. Egami, Biochim. Biophys. Acta, 1970, 209, 289. M. Saito, Y. Furuichi, K. Takeishi, M. Yoshida, M. Yamasaki, K. Arima, H. Hayatsu, and T. Ukita, Biochim. Biophys. Acta, 1969, 195, 299. S. M. Zhenodarowa and M. I. Habarowa, Biochim. Biophys. Acta, 1969, 195, 1 ; S. M. Zhenodarowa and E. A. Sedelnikowa, Biochim. Biophys. Acta, 1969, 195, 8. S. K. Podder and I. Tinoco jun., Biochem. Biophys. Res. Comm., 1969, 34, 569. F. Pochon and A. M. Michelson, Biochim. Biophys. Acta, 1969, 182, 17. J. Simuth, K. H. Scheit, and E. M. Gottschalk, Biochim. Biophys. Acta, 1970, 204, 371. K. H. Scheit, Biochim. Biophys. Acta, 1970, 209, 445. F. Rottman and K. L. Johnson, Biochemistry, 1969, 8, 4354. M. Swierkowski and D. Shugar, Acta Biochim. Polon., 1969, 16, 263 (Chem. Abs., 1969, 71, 102,173). B. Zmudzka, C. Janion, and D. Shugar, Biochem. Biophvs. Res. Comm., 1969, 37, 895. B. Zmudzka, F. J. Bollum, and D. Shugar, J . Mol. Bior., 1969, 46, 169. B. Zmudzka, F. J. Bollum, and D. Shugar, Biochemistry, 1969, 8, 3049. T. Godefroy, M. Cohn, and M. Grunberg-Manago, European J. Biochem., 1970, 12, 236. F. R. Williams and M. Grunberg-Manago, Biochim. Biophys. Acta, 1964, 89, 66. M. Laskowski sen., Adv. Enzymol., 1967, 29, 165. G. M. Richards and M. Laskowski sen., Biochemistry, 1969, 8, 1786.
-
Organophosphorus Chemistry
134 N“pNB.. . . . .pN”p
Nu+n(pN) +pNwp
venom exonuclease
Not surprisingly, 2’,3’-dideoxyadenosine (32) 91 is lethal to E. coli as it blocks DNA synthesis irreversibly. The 5’-triphosphate of (32) is a competitive inhibitor of DNA polymerisation and, since it is incorporated into the end of polynucleotide chains, it terminates polymer synthesis.92
“
O
Y (32)
0 II NH20CCH2CH2S-P -OH I OH (33) 0
Y
0 II AdOP-SEt
II
> AdOP-OH I I OH OH D. Nucleoside Thiophosphates.-Nucleoside phosphorothioate monoesters and dinucleoside phosphate 5’-phosphorothioates have been obtained 93 from S-2-carbamoylethyl phosphorothioate (33) and a suitably protected nucleoside using DCC as condensing agent. The phosphorothioates are readily converted into phosphates on treatment with aqueous iodine.g4 Nucleoside 5’-S-ethyl phosphorothioates are hydrolysed by snake venom phosphodiesterase with the liberation of ethanethiol. H,O/OH-
0, ,OCH2CH,CN
O=P-0 -0’
*// P\
OH
(35)
-0’ (36)
When treated with dilute alkali, the 0-(2-cyanoethyl) esters of 5’-0tosyldeoxyribonucleoside 3’-phosphorothioates (34) cyclise to the corresponding 5’-S,3’-O-phosphorothiolates (35).96 On the other hand, B1
O2
B3 O4
O6
M. J. Robins, J. R. McCarthy jun., and R. K. Robins, Biochemistry, 1966, 5, 224; J. R. McCarthy jun., M. J. Robins, L. B. Townsend, and R. K. Robins, J. Amer, Chem. SOC.,1966, 88, 1549. L. Toji and S. S. Cohen, Proc. Nut. Acad. Sci. U.S.A., 1969, 63, 871. A. F. Cook, J. Amer. Chem. SOC.,1970, 92, 190. A. F. Cook, M. J. Holman, and A. L. Nussbaum, J. Amer. Chem. SOC.,1969,91,6479. J. Nagyvary, S. Chladek, and J. Roe, Biochem. Biophys. Res. Comm., 1970, 39, 878.
135
Phosphates and Phosphonates of Biochemical Interest
polymerisation occurs on warming a solution of (34) in dimethylformamide. Adenosine 3’,5’-O-cyclic phosphorothioate (36) has a lipolytic activity similar to that of the 3’,5’-cyclic phosphateg6but is not a substrate or inhibitor of 3’,5’-cyclic nucleotide phosphodiesterases, and hence could be of pharmacological importance. U.V. and 0.r.d. measurements show that analogues of IMP with P-N and P-S bonds, e.g. (37; X = 0, Y = S), (37; X = S, Y = 0),and (37; X = NH, Y = 0) have the same conformation in aqueous solution as native IMP.97 The analogues are substrates of the IMP-dehydrogenase from Aerobacter aerogenes and kinetic measurements indicate that they bind to the dehydrogenase as dianions. Details have been published g8 for the enzymic synthesis of polyribonucleotides which contain a phosphorothioate backbone. DNA-dependent RNA polymerase can utilise either or both uridine and adenosine 5 ’ 4 (1-thiotriphosphate) [(ppp,-U) or (ppp,-A)] in the presence of a poly d(A-T) template. The rate and extent of the reaction are reduced, however, and are least when both (ppp,-U) and (ppp,-A) are present as substrates. Unlike ATP and UTP, (ppp,-A) and (ppp,-U) can exist in two diastereoisomeric forms (38a and b), and as synthesised each should contain approxi-
Ho-f Y
OEI
,0-CH2-
0,
..p
HS’
“’0-P
P-
(38a)
mately equal amounts of the two isomers. If one diastereoisomer is a very poor substrate for the RNA-polymerase, this might explain the reduced efficiency of the polymerisation reaction. The introduction of a phosphorothioate backbone into polynucleotides has little effect on their physical stability but does reduce their susceptibility to hydrolysis by nucleases. This type of polyribonucleotide is a good inducer of interferon. Treatment of cells with poly(AS-US), the polymer derived from poly(A-U) with a phosphorothioate backbone, can lead to a significant increase in their resistance to infe~ti0n.O~ g6
97 88 99
F. Eckstein and H. P. Bar, Biochim. Biophys. Acta, 1969, 191, 316. A. Hampton, L. W. Brox, and M. Bayer, Biochemistry, 1969, 8, 2303. F. Eckstein and H. Gindl, European J . Biochem., 1970, 13, 558. E. De Clercq, F. Eckstein, and T. C. Merigan, Science, 1969, 165, 1137; E. De Clercq, F. Eckstein, H. Sternbach, and T. C. Merigan, Virology, 1970, 42, 421.
136
Organophosphorus Chemistry
(ppp,-A) has been incorporated into the 3'-end of yeast phenylalanine t-RNA.loO The modified t-RNA could be charged with phenylalanine by aminoacyl t-RNA synthetase and was more resistant to hydrolysis by snake venom phosphodiesterase than the native t-RNA. (ppp,-A) was not a substitute for ATP in the activation of phenylalanine by aminoacyl t-RNA synthetase, but acted as a competitive inhibitor. E. Physical Methods and Analytical Techniques.-The conformations and steric structures of nucleotides and derivatives have been the subject of a recent review.lol The evidence discussed in the review had been derived mainly by X-ray crystallographic techniques for compounds in the solid state; however, 31P n.m.r. spectroscopy can be used to deduce the most favourable conformation adopted by dinucleoside phosphates in aqueous so1ution.lo2 The chromatographic separation on thin layers of DEAE-cellulose of 32P-labelledoligonucleotides up to 50 residues long has been described.lo3 This is a detailed discussion of the combined techniques of electrophoresis and homochromatography, which have been used with such success by Sanger in the determination of the base sequence of 5S-RNA.l0* Polyribonucleotides can be attached to cellulose using DCC as condensing agent. The cellulose-bound polymer can then be degraded in a stepwise fashion from the 3'-end by treatment with periodate and cyclohexylamine followed by alkaline phosphatase.lo6 The characterisation of nucleosides and nucleotides by pyrolysis g.l.c.106~ lo' is an interesting method of analysing trace quantities of material. Pyrolysis of the nucleoside or nucleotide at 800 "C followed by gas chromatography of the decomposition products gives rise to reproducible, unique patterns for each compound. The mass spectrometric analysis of trimethylsilyl derivatives of dinucleotide phenyl boronates has been used to determine their base sequence.lo8 This method appears to give better results than the mass spectrometric analysis of trimethylsilyl dinucleotides,logand should be applicable to the determination of the base sequence in short oligonucleotides. E. Schlimme, F. von der Haar, F. Eckstein, and F. Cramer, European J . Biochem. 1970, 14, 351. lol N. N. Preobrazhenskaya and Z . A. Shabarova, Rum. Chem. Reu., 1969, 38, 111. lo2 M. Tsuboi, S. Takahashi, Y. Kyogoku, H. Hayatsu, T. Ukita, and M. Kainosho Science, 1969, 166, 1505. loS G. G. Brownlee and F. Sanger, European J. Biochem., 1969, 11, 395. loo G. G. Brownlee, F. Sanger, and B. G. Barrell, J. Mol. Biol., 1968, 34, 379. lo5 T.fE. Wagner, H. G. Chai, and A. S. Warfield, J. Amer. Chem. Soc., 1969, 91, 2388. lo8 C. B. Honaker and A. D. Horton, J . Gas Chromatog., 1965, 3, 396. lo' L. P. Turner, AnQlyt. Biochem., 1969, 28, 288. lo8 J. J. Dolhun and J. L. Wiebers, J. Amer. Chem. Soc., 1969, 91, 7755. Io9 D. F. Hunt, C . Hignite, and K. Biemann, Biochem. Biophys. Res. Comm., 1968, 33, 378. loo
137
Phosphates and Phosphonates of Biochemical Interest
2 Coenzymes and Cofactors A. Phosphoenol Pyruvate.-In aqueous solution the hydrolyses of dibenzyl (39) and monobenzyl (40) esters of phosphoenol pyruvic acid proceed by the stepwise loss of benzyl alcohol.llo In the presence of hydroxylamine in aqueous solutions, (39) breaks down to dibenzyl phosphoric acid and
HO’
c
‘COOP(0)(OCH,Ph)2
I1 CH,CO.COOP(O)(OCH,Ph)2
(43) (42)
I
+ PhCH20H
NH,OH/H,O
CH,CCOOH
It
NOH
+ (PhCH@)zP(O)(OH)
(44)
pyruvic acid hydroxamate (41), while (40) gives (41) and benzyl alcohol under the same conditions. The hydrolysis of (39) probably proceeds with the intramolecular formation of a pentacovalent phosphorane, which can react further to give either the cyclic anhydride (42),ll1 or the linear anhydride (43). Hydrolysis of (42) gives (40) which can again form an intramolecular phosphorane. The latter then decomposes to benzyl alcohol and the mixed anhydride of pyruvic and phosphoric acids. The anhydride (43) will react with hydroxylamine with the formation of (41). The cyclic phosphate (44) from ethyl 2-hydroxy-cinnamic acid hydrolyses with C - 0 bond fission; however, the precise mechanism of hydrolysis has not yet been determined.l12 110 111
112
S. J. Benkovic and K. J. Schray, J. Amer. Chem. SOC.,1969, 91, 5653. V. M. Clark and A. J. Kirby, J. Amer. Chem. SOC.,1963, 85, 3705. J. F. Marecek and D. L. Griffith, J. Amer. Chern. SOC.,1970, 92, 917.
138
Organophosphorus Chemistry
Alkyl homologues of PEP can be prepared113 by the Perkow reaction, but the introduction of a bulky group into the PEP molecule reduces the efficiencyof its reaction with pyruvate kinase. This suggests that the binding of PEP might take place at a critically defined site on the ternary enzyme complex 114and that the homologues are too bulky to bind properly at this site. The enzymic carboxylations of PEP by PEP-carboxylase, PEP-carboxykinase, and PEP-carboxytransphosphorylase take place with the addition of carbon dioxide to the same side of the enzyme-bound PEP.l15 This has been taken to indicate that the three enzymes may have a common genetic link.
B. Nicotinamide Coenzymes.-Several NAD+ analogues have been synthesised recently and studied as substrates of oxidoreductases.116-118The reduced form of the analogue containing 4-thio-~-ribose(45) 116 is more fluorescent than native NADH, probably because the molecule assumes an anti-conformation, a view which has been supported by 0.r.d. evidence. The analogue which contains 2,3-dideoxyribose attached to the nicotinamide moiety (46) 117 has fluorescence and absorption spectra which are similar to NAD+ and reacts very slowly with liver alcohol dehydrogenase. Hence the binding of the coenzyme to the molecule must be affected by the presence of the two hydroxy-groups on the ribose ring. Reduction of NAD+ with borohydride leads to a mixture of 1,4- and 1,6-NADH (47) together with the tetrahydro-compo~nd.~~~ Like 1,4NADH, (47) has a maximum in its U.V. spectrum near 345 nm and can be degraded to a derivative with an U.V. maximum at 290 nm. This derivative can be cleaved enzymically to AMP and hence the chromophore must be altered in the nicotinamide rather than the adenine residue.120 It is probable that hydration across the 4,Mouble bond of the nicotinamide ring (48) would account for the change in the absorption spectrum of (47). A similar hydration across the 5,6-double bond of 1,4-NADH (49) has been postulated to account for the change in its absorption spectrum on treatment with acid.121 A pyridine nucleotide, ADP-ribosyl-NAD+, which has been isolated from A . vinelandii 122 may be a precursor of poly-adenosine diphosphate 113
114
116 117 11* 119
121 122
A. E.Woods, J. M. O’Bryan, P. T. K. Mui, and R. D. Crowder, Biochemistry, 1970, 9, 2334. A. S. Mildavan and M. Cohn, J. Biol. Chem., 1966, 241, 1178. I. A. Rose, E. L. O’Connell, P. Noce, M. F. Utter, H. G. Wood, J. M. Willard, T. G . Cooper, and M. Benziman, J. Biol. Chem., 1969, 244, 6130. D.J. Hoffman and R. L. Whistler, Biochemistry, 1970, 9, 2367. C. Woenckhaus and R. Jeck, Annalen, 1970,736, 126. J. F. Biellmann and M. J. Jung, F.E.B.S. Letters, 1970, 7 , 199. S. Chaykin and L. Meissner, Biochem. Biophys. Res. Comm., 1964, 14, 233. K . Chakraverty, L. King, J. G . Watson, and S. Chaykin, J. Biol. Chem., 1969, 244, 4208. R. Segal and G. Stein, J. Chenz. SOC.,1960, 5254; A. G. Anderson and G. Berkelhammer, J. Amer. Chem. SOC.,1958, 80, 992. T. Imai, S. Okuda, and S. Suzuki, J. Biol. Chem., 1969, 244, 4547.
Phosphates and Phosphonates of Biochemical Interest
139
0""""
OCONH2
dN+ Rod
RO
HO
(46)
OH
(45)
HJ3foNH2
Roe H
(47)
(49)
where R
=
Adenosine 5'-pyrophosphoryl
r i b 0 ~ e . lNothing ~~ is known concerning the biological function of this unusual polymer or of the pyridine nucleotide. C. Nucleoside Diphosphate Sugars.-The structure, biosynthesis, and funcand the biosynthesis of polysaccharides 125 have tion of teichoic been the subjects of recent reviews. The number of nucleoside diphosphate sugars which have been discovered and characterised continues to grow lZ3
lZ4
lZ5
T. Shima, S. Hasegawa, S. Fujimura, H. Matsubara, and T. Sugimura, J. Biol. Chem., 1969, 244, 6632; P. Chambon, J. D. Weill, J. Doly, M. T. Strosser, and P. Mandel, Biochem. Biophys. Res. Comm., 1966,25, 638. J. Baddiley, Accounts Chem. Res., 1970, 3, 89. W. Z . Hassid, Science, 1969, 165, 137.
140
Organophosphorus Chemistry
r a ~ i d l y . l ~ ~In - l ~addition ~ to the syntheses of GDP-rhamnose 132 and UDP-galact~samine,~~~ the synthesis of an analogue of UDPGlc derived from 5'-deoxyuridine 5'-pyrophosphonic acid (50) has been achieved.134 00 HO OH
UDPGlc-dehydrogenase will oxidise (50) at the 6-position of the glucose residue and models indicate that the environments round this position in (50) and UDPGlc are very similar. The stereochemistry of the two molecules in the region of the pyrophosphate bridge is dissimilar, however, and pyrophosphatases which cleave UDPGlc do not react with (50). UDP-N-acetylglucosamine 2-epimerase catalyses the conversion of UDPGlcNAc into ManNAc (51) and UDP.136 This reaction is unusual as (51) is released as the free sugar and not as a phosphate or pyrophosphate ester. It is suggested136that the epimerisation of the GlcNAc takes place while the sugar is bound to the enzyme. Oxidation by NAD+ of the 3-hydroxy-group of the enzyme-bound GlcNAc (52), followed by enolisation (53) and reprotonation, can lead to epimerisation of the N-acetyl group to give (54). Reduction of (54) by NADH followed by cleavage of the enzyme-sugar bond liberates (51). The enzyme system in parsley which degrades UDP-glucuronic acid to UDP-pentoses is another which requires NAD+ as c ~ f a c t o r . UDP~~~ apiose (55) is one product of this reaction together with UDP-arabinose and UDP-xylose. Lipids have recently been implicated in saccharide biosynthesis and polyprenol phosphate sugars have been isolated from a number of N. K. Kochetkov, E. I. Budowsky, T. N. Druzhinina, N. D. Gabrieljan, I. V. KomIev, Yu. Yu. Kusov, and V. N. Shibaev, Carbohydrate Res., 1969, 10, 152. N. K. Kochetkov, E. I. Bucovskii, V. N. Shibaev, and Y. Y . KUSOV,Izuest. Akad. Nauk S.S.S.R., Ser. khim., 1969, 1136 (Chem. Abs., 1969, 71, 70,870). 12* A. Garcia Trejo, G . J . F. Chittenden, J. G. Buchanan, and J. Baddiley, Biochem. J . , 1970,117, 637. n9 I. Das, M. A. Wentworth, H. Ide, H. G . Sie, and W. H. Fishman, Biochim. Biophys. Acta, 1970, 201, 375. lao P. Biely and R. W. Jeanloz, J . Biol. Chem., 1969, 244, 4929. lax A. Kobata and V. Ginsburg, J. Biol. Chem., 1970, 245, 1484. la2 G. A. Barber, Biochemistry, 1969, 8, 3692. 133 F. Maley, Biochem. Biophys. Res. Comm., 1970, 39, 371. la* P. C. Bax, F. Morris, and D. H. Rammler, Biochim. Biophys. Acta, 1970, 201, 416. lS5 C. E. Cardini and L. F. Leloir, J. Biol. Chem., 1957, 225, 317; D. G. Comb and S. Roseman, Biochim. Biophys. Acta, 1958, 29, 653. 136 W. L. Salo and H. G. Fletcher jun., Biochemistry, 1970, 9, 882. 13' H. Sandermann jun. and H. Grisebach, Biochim. Biophys. Actn, 1970, 208, 173. 126 12'
Phosphates and Phosphonates of Biochemical Interest UDPGlcNAc
141
+
NHAC (52)
NADH
NADH3
CH,OH Ok
+H+ P
-H+
HO 0
NHAc
-0
____j
HO 0 (54)
NHAc
Organophosphorus Chemistry
142
s o ~ r c e s . ~ ~In* particular, -~~~ an enzyme has been foundl*l in liver which catalyses the transfer of glucose from UDPGlc to dolichol phosphate (56)142and then to a protein. Since dolichol phosphate glucose rapidly breaks down to a 1,6-anhydroglucosan (57) on treatment with alkali, the glucose could be joined to the phosphoryl group with a p-glycosidic linkage.
where R = uridine 5’-pyrophosphoryl
-
UDPGlc + lipid Glc-lipid +protein Glc-protein
-
Glc-lipid + U DP Glc-protein + lipid Glc + protein
---+
0
II
H [CH2C(Me)=CCH,],,CH,CH(Me)CHzCH20POR
I
OH (57) D. Other Nucleotide Coenzymes.-Coenzyme A analogues in which the adenine residue has been replaced by guanine or hypoxanthine have been synthesised 143 by a modification of the phosphoromorpholidate method 138
139
140
141 149
143
A. Wright, M. Denkert, P. Fennessey, and P. W. Robbins, Proc. Nat. Acad. Sci. U.S.A., 1967, 57, 1798. Y . Higashi, J. L. Strominger, and C. C. SweeIey, Proc. Nat. Acad. Sci. U.S.A., 1967, 57, 1878. M. Scher, W. J. Lennartz, and C. C. Sweeley, Proc. Nat. Acad. Sci. U.S.A., 1968, 59, 1313. N. H. Behrens and L. F. Leloir, Proc. Nat. Acad. Sci. U.S.A., 1970, 66, 153. J. Burgos, F. W. Hemming, J. F. Pennock, and R. A. Morton, Biochem. J., 1963, 88, 470. M. Shimizu, 0. Nagase, S. Okada, and Y. Hosokawa, Chem and Pharm. Bull. (Japan), 1970, 18, 313.
Phosphates and Phosphonates of Biochemical Interest
143
A ~conventional synthesis used in the first successful synthesis of C O A . ~ ~ of D-pantothenic acid 4’-phosphate using dibenzyl phosphorochloridate has been pub1i~hed.l~~ 3 Naturally Occurring Phosphonic Acids A. Aminophosphonic Acids.-A study of the uptake of 14C-labelled2-aminoethylphosphonic acid (58) and 2-aminophosphonopropionicacid (59) by Tetrahymena pyriformis has shown 146 that while ( 5 8 ) is incorporated into the phospholipid fraction of the protozoon without degradation, (59) is incorporated as (58). No radioactivity due to (59) could be detected in the phospholipids of Tetrahymena which suggests either that decarboxylation occurs before incorporation or that the decarboxylation of lipid-bound (59) is an extremely efficient process. NH,CHCH,P(O)(OH),
- co2
I
NH,CH,CH,P(O)(OH), (58)
COOH (59)
OH
(ONOH), (60)
Aminophosphonic acids and related compounds can be made volatile by trimethylsilylation and so can be analysed by a combination of g.1.c. and mass This should be useful for the characterisation of trace amounts of phosphoro- and phosphono-lipids which occur in protozoa and in marine organisms. The isolation 14*and synthesis 149-151 of a number of phosphonolipids have been reported during the past year. In particular, ~-2,3-dihydroxypropylphosphonic acid (60) an analogue of L-glycerol-lphosphate has been prepared by an Arbusov reaction on 2,3-0-isoNo mention has been made of the propylidene 34odopropylene glyc01.l~~ stability of (60) and 2-hydroxyphosphonic acids are unstable in aqueous solutions near ne~tra1ity.l~~ Carboxylic esters of 2-hydroxyphosphonic acids are, however, relatively stable under these conditions 154 which should enable phosphonolipids derived from (60) to be prepared and studied. 144 145
J. G. Moffatt and H. G. Khorana, J. Amer. Chem. SOC.,1961, 83, 663. M. Yoshioka, K. Samejima, and Z. Tamura, Chem. and Pharm. Bull. (Japan), 1969, 17, 1265.
148 14’ 148
149
15* 151 152
15s 154
J. D. Smith and J. H. Law, Biochemistry, 1970, 9 , 2152. K. A. Karlsson, Biochem. Biophys. Res. Comm., 1970, 39, 847. T. Hori, M. Sugita, and 0. Itsaka, J , Biochem. (Japan), 1969, 65, 451. E. Baer and K. V. J. Rao, Canad. J. Biochem., 1970, 48, 184. E. Baer and S. K. Pavanaram, Canad. J. Biochem., 1970,48,221. E. Baer and G. R. Sarma, Canad. J. Biochem., 1969,47, 603. E. Baer and H. Basu, Canad. J. Biochem., 1969, 47, 955. W. Vogt, Tetrahedron Letters, 1970, 1281. B. D. Place. Ph.D. Thesis, University of Warwick, 1969.
1 44
Organophosphorus Chemistry
B. Phosphonomycin.-A new broad-spectrum antibiotic, phosphonomycin, . ~ ~antibiotic, ~ which can has been isolated from Streptomyces f r ~ d i a e The be administered orally, attacks the cell walls of bacteria but shows little toxicity to the host. The structure of phosphonomycin has been shown to be (- )-(1 R, 2S)-1,2-epoxypropylphosphonicacid (61) l S 6by a combination
Me0 H-j+ Me
H P (0)(0Me) 2 OMe
/
Ag,O/MeI
MeC = CMgBr + ClP(O)(OBu),
-
MeC s CP(O)(OBu),
I..
H,/Lindlar catalyst
(a) HCI
(61)
' (b) Hzo2
Me
P(O)(OBu),
111 MeCH2CH0 166
166
D. Hendlin, E. 0. Stapley, M. Jackson, H. Wallick, A. K. Miller, F. J. Wolf, T. W. Miller, L. Chaiet, F. M. Kahan, E. L. Foltz, H. B. Woodruff, J. M. Mata, S. Hernandez, and S. Mochales, Science, 1969, 166, 122. B. G. Christensen, W. J. Leanza, T. R. Beattie, A. A. Patchett, B. H. Arison, R. E. Ormond, F. A. Kueld jun., G . Albers-Schonberg, and 0. Jardetsky, Science, 1969, 166, 123.
Phosphates and Phosphonates of Biochemical Interest
145 of spectroscopic techniques and by degradation to dimethyl threo-l,2dimethoxypropylphosphonate(62). Final confirmation of the structure of (61) was provided by its synthesis from propynylmagnesium bromide and di-n-butyl phosphorochloridate. Additional evidence for the cis-relationship of the methyl and phosphonyl groups came from the nuclear Overhauser effect which was observed for the methyl protons on irradiation of the phosphorus nucleus. Phosphonomycin reacts irreversibly with pyruvate-UDPGlcNAc transferase of bacteria 155 possibly by the formation of a covalent bond between the active site of the enzyme and the epoxide function. Phosphonomycin might be expected to react with a variety of possible active sites of enzymes because in addition to being a water-soluble epoxide it is also a P-XYZ phosphorylating agent.167 4 Oxidative Phosphorylation One weakness of the chemical theory of mitochondria1 oxidative phosphorylation is that in spite of intensive efforts, no ‘energy rich’ intermediates have yet been isolated. This failure could be either because the intermediates do not exist 158 or because they break down during isolation. The production of ATP by the aerobic oxidation of di-imidazolylferrohaemochrome in solution in NN-dimethylacetamide containing imidazole, orthophosphate, and ADP lKS has led to the suggestion that phosphorylated imidazole derivatives may be involved in respiratory oxidative phosphorylation.160 Oxidation of a cytochrome held in a position close to a phospholipid or phosphoprotein could lead first to an unstable phosphorylated imidazole radical and then to an N-phosphorylated imidazole. The latter could react with orthophosphate to give a phosphoric anhydride (63) which in turn could convert ADP into ATP. According to this theory, inhibitors of electron transport would form complexes with electron carriers and hence prevent electron transport, while uncouplers would react with the radical precursor of N-phosphoryl imidazole and so prevent phosphoryl transfer.
where ROH 16‘
15* 169
le0
= phospholipid
or phosphoprotein
V. M. Clark and D. W. Hutchinson, Prugr. Org. Chem., 1968, 7 , 75. P. Mitchell, Nature, 1961, 191, 144. W. S. Brinigat, D. B. Knaff,and J. H. Wang, Biochemistry, 1967,6, 3 6 ; T. A. Cooper, W. S. Brinigar, and J. H. Wang, J. Biol. Chem., 1968, 243, 5854. J. H. Wang, Accounts Chem. Res., 1970, 3, 90; J. H. Wang. Science, 1970, 167, 25.
146
Organophosphorus Chemistry
Other systems which have been proposed as models for oxidative phosphorylation are acylated hydroquinones (64) 161*le2 and thioethers For example, such as (65), (66), or 5'-deo~y-5'-methylthioadenosine.~~~ ATP has been formed by the bromine oxidation of a solution of AMP, (65), and orthophosphate in pyridine, when the products include the sulphoxide of (65). This suggests that a sulphonium intermediate (67) may be formed initially between (65) and a bromonium ion. Interaction of (67) with phosphate followed by phosphoryl transfer to ADP leads to ATP and the sulphoxide. Haemin has been used in place of bromine in the oxidative synthesis of ATP from ADP, orthophosphate, and either tocopherol or thioglycollic acid.l**
fY
MeSCH,CH,CHCOOH I NHAc
HO
RSR
+ Brf
R ___+
\
R$R
%
I
Br
ATP
R-S-O-P< / Br
n W 0 II OH OH
+ Br- + RoSO
5 Sugar Phosphates A. Pentoses.-/bRibofuranose 1-phosphate (68) is the only sugar phosphate which is formed in the reaction between D-ribose, orthophosphate, and cyanogen or cyanamide.ls5 This method has been used to prepare l80-label1ed(68) le6and since it has been found that the oxygen atom of the P-0-C bond was derived mainly from the ribose, the phosphorylating agent must be an imidoyl phosphate derived from the addition of orthophosphate to cyanogen.le7 Ribose 5-phosphate 1-methylenediphosphonate(69) has been isolated 168 V. M. Clark, M. R. Eraut, and D. W. Hutchinson, J . Chem. SOC.(C), 1969, 79. T. Wieland and H. Aquila, Chem. Ber., 1969, 102, 2285. le3 D. 0. Lambeth and H. A, Lardy, Biochemistry, 1969, 8, 3395. 16* E. Bauerlein and T. Wieland, Chem. Ber., 1970, 103, 648. le6 M. Halmann, R. A. Sanchez, and L. E. Orgel, J. Org. Chem., 1969,34, 3702. lS6 M. Halmann and H. L. Schmidt, J . Chem. SOC.(C), 1970, 1191. 18' R. Lohrmann and L. E. Orgel, Science, 1968, 160, 64. 16* A. W. Murray, P. C. L. Wong, and B. Friedrichs, Biochem. J., 1969, 112, 741. 161
lsa
147
Phosphates and Phosphonates of Biochemical Interest -*
'
Y
o
HO
2
0
H o y ~ ~ o P ~ o ~ ~ o H ~
+ H,POj + (CN)2
H
OH
HO
OH (68)
(69) from the reaction between ribose 5-phosphate and 5'-adenylyl methylenediphosphonate 16u which is catalysed by 5-phosphoribosyl pyrophosphate synthetase from Ehrlich ascites-tumour cells. The isolation of (69) is direct confirmation that the reaction proceeds with a one-step pyrophosphate transfer 170 rather than with two consecutive phosphate transfers. Ribose 5-phosphorothioate, which can be prepared by the action of thiophosphoryl chloride on ribose, is also a substrate for the pyrophosphate synthetase.lsU B. Hexoses.-/h-Glucopyranose 1-phosphate (70) has been prepared by addition of dibenzyl phosphoric acid to 3,4,6-tri-O-acetyl-l ,Zanhydro-aCH,OH (a) (PhCH,O),P(O)(OH),
(b) removal of protecting groups
(71) CH,OAc
OCCI,
II
0
OCOCCI,
(73) 170
T. C. Myers, K. Nakamura, and J. W. Flesher, J . Amer. Chem. SOC.,1963, 85, 3292. H. G. Khorana, J. F. Fernandes, and A. Kornberg, J. Bid. Chem., 1958, 230, 941.
148
Organophosphorus Chemistry
D-glucose (71) followed by the removal of protecting groups.171 The fully protected a-anomer (73) of (70) has been obtained172 by treatchloride (72) ing 3,4,6-tr~-O-acetyl-2-O-(tr~ch~oracetyl)-~-~-glucopyranosyl with silver dibenzyl phosphate. Neighbouring group participation by the trichloracetyl group in the 2-position does not appear to affect the steric course of this reaction, and migration of the phosphoryl group is prevented if the benzyl groups are removed before the ester groups from the fully protected sugar phosphate. The stereospecific formation of D-glucose 6-phosphate (74) from D-fructose 6-phosphate catalysed by phosphoglucose isomerase has been studied by lH n.m.r. and it has been shown that the transformation occurs by a combination of C-2 proton exchange with solvent and hydride transfer from C-1 of the ketose to C-2 of the aldose. A study of the mechanism of phosphoribose isomerase by this technique was not so successful, as the n.m.r. spectrum of D-ribofuranose 5-phosphate is complex and only the signals due to C-2 protons are readily distinguishable.
OH (74)
The coupled reduction of NADP+ by (74) which is catalysed by glucose 6-phosphate dehydrogenase174 has been used to follow the very rapid mutarotation of (74). The enzyme is specific for the p-anomer and the rate of mutarotation of (74) is 240 times faster than that for a-D-glucose measured polarimetrically under the same conditions. The accelerated rate of mutarotation is probably due to intramolecular catalysis by the phosphate group in (74). The mass spectrometric behaviour of volatile trimethylsilyl sugar phosphates175 has been described in detail and a summary of the ions which are of particular use in their identification has been 6 Inositol Phosphates and Phospholipids A. Inositol Phosphates.-Reviews have recently appeared on inositol phosphates 17' and p h o s p h a t i d e ~ . ~Quebrachitol ~~ (1-~-2-O-methyl-chiro171 17a
173 174
17L 178
177
178
C. L. Stevens and R. E. Harmon, Carbohydrate Res., 1969, 11, 99. C. L. Stevens and R. E. Harmon, Carbohydrate Res., 1969, 11, 93. M. S. Feather and M. J. Lybyer, Biochem. Biophys. Res. Comm., 1969, 35, 538. J. M. Bailey, P. H. Fishman, and P. G. Pentcher, Biochemistry, 1970, 9, 1189. F. Eisenbert jun. and A. H. Bolden, Analyt. Biochem., 1969, 29, 343. M. Zinbo and W. R. Sherman, J . Amer. Chem. SOC.,1970, 92, 2105. S. J. Angyal, B. M. Luttrell, A. F. Russell, and D. Rutherford, Ann. N . Y. Acad. Sci., 1969, 165, 533. B. A. Klyashchitskii, S. D. Sokolov, and V. I. Shvets, Russ. Chem. Rev., 1969,38, 345.
MeNH CO * CH :C: CPhz (100) 28%
Ml o:
ArCHO
(95)
ArCH:C:C:CPh, (101) 60-70%
Ph&: C: 0
[PhZC:C :C :C :CPh,], (102)
aromatic aldehydes it gave the butatrienes (101) and with methyl isocyanate followed by water gave the amide (loo), perhaps uia the imine (99). A dimer of the pentatetraene (102) was obtained from the ylide (95) and diphenylketen. The allenic salt (94) did not add methanol or t-butyl sulphide, but with aniline the salt (96) was obtained. This with phenyllithium gave the imino-stabilised ylide (97) from which the amino-diene (98) was obtained on treatment with 3,4-dichlorobenzaldehyde. Ph,$ -CH:C(OEt),
BF,-
NaNH 4 Ph,P :C :C(OEt), NH,
(103)
/'
RICH,. CO * R2
RZ= Ph, Me, OEt
J
Ph3P:CH.C(OEt):CR1.CO-R2
Fluorenone
a J.
/
\
(106)
I
PhCHO
PhCH :CH *C(OEt):CR' .CO. R2 (1 07)
tr,o
-I I i.
OEt
Ph
OEt (105)
65%
Ylides and Related Compounds
175
With fluorenone the 2,2-diethoxyvinylidene-ylide(103) gave the expected allene (104), isolated as the dimer (105), but the reaction with carbonyl compounds containing an a-methylene group was quite different.48 Michael addition followed by the elimination of ethanol gave the stable ylides (106). These in olefin synthesis with benzaldehyde gave the ketones (107), hydrolysis of which led to the /3-diketones (108). In the n.m.r. spectrum of the ylides (106; R1= H), the y-proton was split into a doublet by the phosphorus ( 4 J p= ~ 6.5 Hz). 3 Selected Applications of the Wittig Olefin Synthesis A. Natural Products.-(i) Prostaglandins. In syntheses of prostaglandins E2 and F2ar (both dl 4 9 ~6o and optically active "') the cis-olefinic side-chain was introduced using the ylide (1 10) generated in dimethyl sulphoxide. Thus the lactol (109) gave the acid (111) in > 80% yield. The ylide (110) under these conditions also gave cis-olefins with simple aldehydes.
PH + Ph,P:CH-(CH,),.C02-
&C5H,,
RO
OR
\DMSO
In the course of a synthesis of (+)-prostaglandin E3 methyl ester, the aldehyde (1 12) with the acetylenic ylide (1 13) gave the acetylene (1 14).62 The tributylphosphorane (1 16) was used in a synthesis of ( k )-prostaglandin El methoxime in order to introduce the required side-chain into the aldehyde (1 15).53 (ii) Isuprenuids. A general method for the elaboration of isoprenoid chains, one unit at a time, uses the ylide from the salt (117) followed by hydration 4s 49
50 51
62
53
H. J. Bestmann and R. W. Saalfrank, Angew. Chem. Internat. Edn., 1970, 9, 367. E. J. Corey, N. M. Weinshenker, T. K. Schaaf, and W. Huber, J. Amer. Chem. SOC., 1969,91, 5675. E. J. Corey and R. Noyori, Tetrahedron Letters, 1970, 31 1. E. J. Corey, T. K. Schaaf, W. Huber, U. Koelliker, and N. M. Weinshenker, J. Amer. Chem. SOC.,1970,92, 397. U. Axen, J. L. Thompson, and J. E. Pike, Chem. Comm., 1970, 602. N. Finch and J. J. Fitt, Tetrahedron Letters, 1969, 4639.
176
Organophosphorus Chemistry
H
A
w
CH :CH-CH,.CiC-Et
C02Et I
76%
>-
74% --+
21% all-fruns
39X all-tram
Ylides and Related Compounds
177
of the terminal acetylene in the product, a mixture of cis- and tvansisomers.54 The ylide (118) allows a similar addition of Clo-units, a process ~ ~ method has which can be repeated after hydrolysis of the a ~ e t a l .This been used in the synthesis of chlorobiumquinone. The high proportion (65%) of the cis-olefin formed in the reaction of the ylide from the salt (119) with the aldehyde (120) has been ascribed to stabilisation of the erythro-betaine by orbital overlap, as in (121).56
Methyl natural bixin (122) has been synthesised as The labelled (3H) ester phosphorane (123) has been used to prepare the thioethers shown for biosynthetic studies in Anthemis species.s8 The reaction of the ester phosphorane (125) with a-halogenocarbonyl compounds has been applied to the elaboration of steroid side-chains in isocardenolide synthesis, i.e. (124) -+ (126).60 A detailed study has been made of the reactions of 20-0x0-steroids with methoxymethylenetriphenylphosphorane.61 Isopropylidenetriphenylphosphoranehas been used in the synthesis of trans-2,6-farnesol and of trans-nerolidol and, labelled with 14C, in the preparation of 14C-labelled ( + )-trans-chrysanthemum mono- and dicarboxylic acids and related Methylenation with methylenetriphenylphosphorane has been used in b4 66 66
67 68
6a
6o
62
6s
K. Sato, S. Inoue, and S. Ota, J . Org. Chem., 1970, 35, 565. W. E. Bondinell, C. D. Snyder, and H. Rapoport, J . Amer. Chem. SOC.,1969,91,6889. J.-L. OlivB, M. Mousseron-Canet, and J. Dornand, Bull. SUC.chim. France, 1969,3247. G . Pattenden, J. E. Wray, and B. C. L. Weedon, J . Chem. SOC.( C ) , 1970, 235. F. Bohlmann and W. Skuballa, Chem. Ber., 1970, 103, 1886. H. J. Bestmann, K. Rostock, and H. Dornauer, Angew. Chem. Internat. Edn., 1966, 5 , 308. G. R. Pettit, B. Green, A. K. Das Gupta, P. A. Whitehouse, and J. P. Yardley, J . Org. Chem., 1970, 35, 1381. G. R. Pettit, G. L. Dunn, and P. Sunder-Plassman, J. Org. Chem., 1970, 35, 1385. 0. P. Vig, J. C. Kapur, and C. K. Khurana, J. Indian Chem. Suc., 1969, 46, 505. L. Crombie, C. F. Doherty, and G. Pattenden, J . Chem. Suc. (C), 1970, 1076.
178
Organophosphorus Chemistry
/ Ph,PH
Br-
I
(i) NaBH, (ii) Ph$H Br(iii) Base
Ph,P: CH* C0,Me (1 23)
+ Me. C i C. C(SMe) :CH-C i C*CHO
-
Me. Ci C*C(SMe):CH-Ci C. CH: CH*. C0,Me c, t
Ylides and Related Compounds 179 the synthesis of ( f)-steviol methyl ether,64dihydr0-5,6-norcaryophyllene,~~ ( f )-nootkatone,6s ( -)-phyll~cladene,~~ and ( +)-~-cadinene.~~ In the last synthesis, the cis-decalone (1 27) gave the trans-decalin (128), epimerisation via the enol form preceding methylenation. To avoid a similar isomerisation in the synthesis of a racemic boll weevil pheromone, the ketone (129) was added slowly to an excess of the ylide in THF-DMSO (4 : 1); only 3% of the trans-acid was formed.sQ
-( 129)
Me
80%
Among other isoprenoids synthesised using phosphorus ylides are H. cecropia juvenile hormone,70 ( 5 ) - ~ i r e n i n , ~a ~ p e r o n o n e ,(~ ~)-aand 3,4,3’,4’-bi~dehydro-p-carotene.~* (iii) Miscellaneous. ( f)-Dictyopterene A (130) was obtained as together with an equal amount of the cis-isomer. Girinimbine (131) was synthesised 76 by an application of the procedure of Schwei~er.~? Ylides were also used in syntheses of di-0-methylstrepsilin 78 and of (-)-epiallogibberic acid.7Q
+
64 6s 66
67 68
69
70
71 72 75
74 76 7e
77
78 7g
K. Mori, Y.Nakahara, and M. Matsui, Tetrahedron Letters, 1970, 2411. J. L. Gras, R. Maurin, and M. Bertrand, Tetrahedron Letters, 1969, 3533. J. A. Marshall and R. A. Ruden, Tetrahedron Letters, 1970, 1239. R. A. Appleton, P. A. Gunn, and R. McCrindle, J. Chem. SOC.(C), 1970, 1148. M. D. Soffer and L. A. Burk, Tetrahedron Letters, 1970, 211. R. Zurfliih, L. L. Dunham, V. L. Spain, and J. B. Siddall, J. Amer. Chem. Soc., 1970, 92, 425. G. W. K. Cavill, D. G. Laing, and P. J. Williams, Austral. J. Chem., 1969, 22, 2145. J. J. Plattner, U. T. Bhalerao, and H. Rapoport, J. Amer. Chem. SOC.,1969, 91, 4933. G. Pattenden, Tetrahedron Letters, 1969, 4049. L. Bartlett, W. Klyne, W. P. Mose, P. M. Stopes, G. Galasko, A. K. Mallams, B. C. L. Weedon, J. Szabolcs, and G. Tbth, J. Chem. SOC.(C), 1969, 2527. J. D. Surmatis, A. Walser, J. Gibas, and R. Thommen, J. Org. Chem., 1970, 35, 1053. K. C. Das and B. Weinstein, Tetrahedron Letters, 1969, 3459. N. S . Narasimhan, M. V. Paradkar, and A. M. Gokhale, Tetrahedron Letters, 1970, 1665. E. E. Schweizer, E. T. Shaffer, C. T. Hughes, and C. J. Berninger, J. Org. Chem., 1966, 31, 2907. J. D. Brewer and J. A, Elix, Tetrahedron Letters, 1969, 4139. K. Mori, M. Matsui, and Y. Sumiki, Tetrahedron Letters, 1970, 429.
180
Organophosphorus Chemistry
+ Ph,P:CH.CaHQ
Ether
cC4HQ
+ + Ph,P.CH,*CMe:CH,
C1-
CHO
Me B. Carbohydrates.-Among ylides, Ph3P:CHR (1 32), used in conventional olefin synthesis with protected aldehydu-sugars are those with R = MeYBo BU,~OCH:CH2,81 C H : C H O R ,CHOYB1 ~~ SMe,82 C O . C O , B U ~ ,and ~ ~ the (131)
11%
"k
II 0 (132a) R = H or Ph
(1 33)
CH*SPh
-
D-Arabhose i- Ph,P: CH SPh
DMSO.
11
HgCI,
__j
HgO
2-Deoxy-~-glucose 50%
H+H H OH
Hzo
CH20H
(135)
83
72%
Yu. A. Zhdanov and V. G. Alekseeva, Zhur. obshchei Khim., 1969,39,405. Yu. A. Zhdanov and V. G. Alekseeva, Zhur. obshchei Khim., 1969, 39, 112. J. M. J. Tronchet, N. Le-Hong, and Melle F. Perret, Helu. Chim.Acta, 1970, 53, 154; J. M. J. Tronchet and J. M. Chalet, ibid., p. 364. N. K. Kochetkov, B. A. Dmitriev, and L. V. Backinowsky, Carbohydrate Res., 1969, 11, 193.
Ylides and Related Compounds
181 stable ylides (132a).84 The acetonylidenephosphorane (132 ; R = CO Me) with partially protected 85 and with free aldoses 86 in D M F at 90-100 "C for 30 h gave the expected unsaturated ketones as internal acetals. Under the same conditions the ylide (132 ; R = p-Me0 - C6H, CO) with partially protected aldoses gave either furans, e.g. [(133); 13x1 from 3-0-methylglucose, or anhydro-derivatives with y- or &oxide rings, e.g. l(134); 11x1 from 3-0-benzylglucose.87 The ylide (133; R = SPh) with unprotected aldoses in DMSO gives unsaturated thioethers in high yields,88e.g. (135) from D-arabinose, which are readily converted into 2-deoxyaldoses. The protected nucleoside aldehyde (136) on refluxing in ethanolic sodium ethoxide with the salt (1 37) gave the acids (1 38) and (139), together with their (138) and its ester were probably formed by rearrangement of the primary a,P-unsaturated ester, while the other products may have arisen via the cx,p-unsaturated aldehyde.
-
-
0
-t
OH
C. Miscellaneous.-Full details have appeared of the self-condensation of the ylide from the salt (140). Minor products such as (141) and (142) can be rationalised in terms of the formation of acetaldehyde and 5-methylfurfuraldehyde as shown. The dibenzocyclo-octatetraene (144) and the tribenzo-[ 12lannulene (145) were isolated 91 from the self-condensation of the ylide from the salt (143) but no dimer of benzocyclobutadiene, which would result from intramolecular olefin synthesis, was detected. Among olefins prepared by methylenation are (146) 92 and (147).93 f4 85
86
ns 8''
so O1
g2
O3
R. E. Harmon, G. Wellman, and S. K. Gupta, Carbohydrate Res., 1969, 11, 574. Yu. A. Zhdanov and V. A. Polenov, Zhur. obshchei Khim., 1969,39, 1124. Yu. A. Zhdanov and V. A. Polenov, Zhur. obshchei Khim., 1969, 39, 1121. Yu. A. Zhdanov and V. A. Polenov, Zhur. obshchei Khim., 1969, 39, 119. H. J. Bestmann and J. Angerer, Tetrahedron Letters, 1969, 3665. P. Howgate, A. S. Jones, and J. R. Tittensor, Carbohydrate Res., 1970, 12, 403. J. A. Elix, Austral. J. Chem., 1969, 22, 1951. C. Brown and M. V. Sargent, J . Chem. SOC.( C ) , 1969, 1818. A. P. Krapcho and D. E. Horn, Tetrahedron Letters, 1969, 4537. J. M. Conia and J. M. Dems, Tetrahedron Letters, 1969, 3545.
7
182
Organophosphorus Chemistry
Me-(-&HO
Me
t CH,.CHO
MeCH:CH
a /
Reflux
-
CH,*PPh,
26.3%
(144)
(143)
+
(145)
+
0.41%
KOBU~ 7
+Ph3P*CH3
PhLi
xH x H2C
(146) 20%
+ Ph,P.CH, +
(Pri),O
NaoPri
(147) 60%
Ylides and Related Compounds
183
The polyenyl-substituted furans and thiophens (148) and (149) have been prepared as A number of aromatic and heterocyclic aldehydes have been condensed Q5 with the ylide from the salt (150), and the aldehydes (1 5 1) gave the corresponding olefins with the ylides (1 52), each vinyl thioether being obtained as geometrical isomers.96 A Wittig reaction between the a-diketone (153) and the bis-ylide (154) gave Q7 benzo[3,4]cyclobuta[1,2-c]thiophen (1 55).
4 Synthetic Applications of Phosphonate Carbanions In benzene, THF, or dimethoxyethane the cyanomethylphosphonate (1 56; R = CN) and aromatic aldehydes in the presence of sodium hydride gave the same thermodynamic mixtures of cis- and trans-olefins, independent of the order of addition of reagents. However, in hexamethyl phosphoric triamide (HMPT), while the thermodynamic mixture was obtained on addition of the aldehyde to the phosphonate in HMPT containing one mole of sodium hydride, a kinetically controlled mixture of isomers resulted from addition of the base to the phosphonate and an excess of aldehyde in HMPT.QS J. W. Van Reijendam, G. J. Heeres, and M. J. Jannsen, Tetrahedron, 1970, 26, 1291. T. R. Pampalone, Org. Prep. Procedures, 1969, 1, 209. u' H. Saikachi and S. Nakamura, Yakuguku Zusshi, 1969, 89, 1446. 97 P. J. Garratt and K. P. C. Vollhardt, Chem. Comm., 1970, 109. J. Seyden-Penne and M. G. Lefebvre, Compt. rend., 1969,269, C, 48. O4
95
Organophosphorus Chemistry
184
Steroidal a-acetoxy-ketones of part structure (157) with the anion from (156; R = CN) gave the nitriles (158), together with the iminolactone hydrochlorides (1 59) derived from the isomeric nit rile^.^^ The same anion reacted with the less-hindered carbonyl of substituted succinirnides to give loolargely the trans-isomers, e.g. (160). ( Et0)ZP( : O ) CH2.R
- Irr" 9
(1 56)
CH,OAc
I
1
6
+ (EtO),P(:O)*CH.CN
O
CH,OAc
THF
(157)
+
(158)
(159)
Ph Me
p0
~
+ (156)
(MeOCH,),. NaH
~
~
I
Me
'
;yJ--N o I Me
H
(160) 46%
+
6% cis
Use of the phosphonate (156; R = SMe) in olefin synthesis lol has been reinvestigated.lo2 Successive treatment of (156; R = SMe) with butyllithium and an alkyl iodide gave the (1 -methylthio)alkylphosphonates (1 6 1). The lithio-derivatives of these reacted with carbonyl compounds to give adducts which decomposed at 50 "C in THF to give substituted vinyl methyl sulphides (162). These are readily converted into ketones on mercury-catalysed hydrolysis. (EtO),P(:O)-CHRl=SMe
(i) BuLi
(EtO),P(:O)-CRl(SMe).C(6)R2R3Li+
(161)
I
i"'" (EtO),PO,- Lif
+ (MeS)RIC:CR2R3 (1 62)
Among other substituted phosphonate esters used in olefin synthesis G . R. Pettit, C. L. Herald, and J. P. Yardley, J. Org. Chem., 1970, 35, 1389. C. Gadreau and A. Foucaud, Compt. rend., 1970, 270, C , 1430. lol M. Green, J . Chem. Soc., 1963, 1324. l o 2 E. J. Corey and J. I. Shulman, J . Org. Chem., 1970, 35, 777. @e
loo
185
Ylides and Related Compounds
were (156; R = CH:CH.CO2Me),lo3 (156; R = S0,Me),lo4 (156; R = a-naphthyl),lo5 (156; R = CO ~C5H11),106 (163),lo7 and (164).lo8 The enamines from the last were readily hydrolysed to a-diketones. Me
I
NaH
(R1O),P( :0)-CH(NR2R3).CO*R4+ R5*CH0 ------+ (164)
-
R5* CH :C(NR2R3) CO R4
I
H+-H20
-
R5*CH2*CO CO * R4
The ambident anions (I 65), formed from y-substituted allylphosphonates, with carbonyl compounds gave the expected olefins (166) via coupling at the a-position when X was OEt, OPh, SPh, or NR2,109but products derived from both a- and y-coupling when X was halogen.llo Only the
.
( Et0)2P( :O).C -C -C X I
I
+
R" CO - R4 *
R3R4C:CH * CR1:CR2X
I
I
X = CI, Br 2 H
R'
R2 R3 I I (Et0)2P(:O)*CH:CH-C-C-R4 \ / 0 (167)
+
(166; X = C1, R1 = H)
+
(1 68) R. S. Burden and L. Crombie, J. Chem. SOC.( C ) , 1969, 2477. Io4 I. Shahak and J. Almog, Synthesis, 1969, 1, 170. I o 5 W. E. Hahn and J. Zimnicki, Roczniki Chem., 1969, 43, 95. l o 6 E. J. Corey, Z. Arnold, and J. Hutton, Tetrahedron Letters, 1970, 307. '07 D. Redmore, J. Org. Chem., 1969, 34, 1420. H. Gross and W. Buerger, J. prakt. Chem., 1969, 311, 395. log G. Lavielle and G. Sturtz, Bull. SOC.chim. France, 1970, 1369. G. Lavielle, Compt. rend., 1970, 270, C, 86. lo3
Organophosphorus Chemistry
186
epoxides (1 67), from y-coupling, and the dihydrofurans (1 68), from a-coupling, were observed in protic solvents. The ambident anion from the allylphosphonamide (169) gave entirely addition to the y-site but that from the cyclic phosphonamide (170) gave with ketones the /3-hydroxyphosphonamides (1 71).ll1 These on heating formed dienes. Both the a-position of the phosphonamide carbanion and the carbonyl group must be unhindered for selective addition to the a-site to occur.
-
CH, :CH CH, * P( :O)(NMe2),
(i) BuLi
(169)
Me,C(OH).CH,-CH:CH.P(:O) (NMe2)2 Me Me
Me
R1R2C: CHCH:CH,
Alkyl-pyrrolones (172) were obtained on intramolecular condensation of the phosphonates (173) prepared as shown.l12 The dihydropyridone (1 75) was similarly obtained starting from diacetoneamine (1 74), but N-ethyldiacetoneamine could not be condensed with the acid-phosphonate. R2-C(OEt), I
R3-C
/ \
R4 NH2
ll1 112
+
R’ I HC-P(:O)(OEt)Z I C02H
-
R1 R2-C(OEt),
I
( 173) E. J. Corey and D. E. Cane, J . Org. Chem., 1969,34, 3053. G. Stork and R. Matthews, Chem. Comm., 1970, 445.
1
HC-P( :O)(OEt),
I
c=o
Ylides and Related Compounds
187
M e y o NH,
+ H02C*CH,*P(:O)(OEt)2
Me &Me
(174)
Me M
eH
60
(1 75)
Benzylideneaniline and the phosphonate (1 76) in the presence of sodamide gave the kinetically-controlled erythro-isomer of (1 77) in ether at - 33 "C but the thermodynamically-controlled threo-isomer in ether at + 10 "C or in liquid ammonia.l13 p-Me.C,H,-CH,.P(:O)(OEt),+ C,H,.CH:N-Ph (1 76)
NaNHn
PhCH(NHPh). CHAr[P( :O)(OEt),] (177)
5 Ylide Aspects of Iminophosphoranes The sulphonyliminophosphoranes (1 78) have been obtained 114 by heating with copper powder the adducts from phosphines and NN-dichlorosulphonamides.
+
-
Ar-SO,-NCI, R3P R = Bu or Ph
[I
-----&+ Ar.SO,-N:PR, (178)
Iminotriphenylphosphorane (1 79) reacts exothermically with nitriles to give the stabilised iminophosphoranes (1 80). Other reactions of (1 79) leading to stable phosphoranes are given in the formulae.lls Tetrazoles (182) are formed when the iminophosphoranes (181; R1 = a-naphthyl, /I-naphthyl, Ph, Ph CH, * CH,, or a-pyridyl) are treated either with an acyl azide or with an acyl chloride followed by sodium azide.l16 Only when trifluoroacetic anhydride was used was the imine (183) isolated. The iminophosphorane (1 79) with acyl azides gave the acyliminophosphoranes (184). No tetrazoles were obtained from the iminophosphoranes 113 114 116
116
M.Kirilov and J. Petrova, Tetrahedron Letters, 1970, 2129. A. Schonberg and E. Singer, Chem. Ber., 1969, 102, 2557. A. S. Shtepanek, E. N. Tkachenko, and A. V. Kirsanov, Zhur. obshchei Khim., 1969, 39, 1475. E. Zbiral and J. Stroh, Annalen, 1969, 725, 29.
Organophosphorus Chemistry
188
T
-
RCN R = Ph, CCI,, CF,, etc.
Ph,P:N*CO-CF,
(29)
+ 4HCI
Under milder conditions ( G 6 5 "C) only khree moles of hydrogen chloride are lost, leaving the P-substituent, NHPC1,Cl-, in (29). As might be anticipated, the trichlorophosphazenyl group in (29) undergoes solvolysis with formic acid, leaving the ring intact: -N=PC13
+ HCO,H
-NHP(:O)CI,
+ HCI+CO
Cyanamide does not, however, give a cyclic product under similar conditions : H,NCN
+ 3PC&
[Cl,P=N- c(cI)=N-PCI,]+[PcI,]-
3. 2HC1
A route 66 to unsymmetrical cyclophosphazatrienes has also been described : RC(NHZ)=N.CI
+ R'ZPNCO
(32)
> [RC(NH,)= NPR1,NCO] +C1-
(31)
)) RS )> RO Cl. Microwave spectra obtained from compounds in magnetic fields of around 30,000 G show first- and second-order Zeeman effects from which the molecular quadrupole moments may be obtained.ls2 In this way a comparison of charge distribution may be obtained. Thus PF3 has a large positive quadrupole moment which is decreased in POF3 by the opposing effect of the PO group.
>
5 Electronic Spectroscopy The importance of 3d orbitals on electronic transitions and other physical properties has been examined by semi-empirical MO calculation^.^^^ The agreement between computed and observed properties was improved when the 3d orbit exponent z was included in the basic set but for phosphorus compounds it was relatively insensitive to the precise value of z over a modest range centred at 1-4. The photochemical rearrangements of acetylphosphonates (123) which 0
(123) lS1
L. S. Khaikin and L. V. Vilkov, J. Struct. Chem., 1969, 10, 614. P. Mauret and J. P. Fayet, Bull. SOC.chim. France, 1969, 2363. R. G. Stone, J. M. Pochan, and W. J. Flygare, Inorg. Chem., 1969, 8, 2647. W. W. Fogleman, D. J. Miller, H. B. Jonassen, and L. C. Cusachs, Znorg. Chem., 1969, 8, 1209.
Organophosphorus Chemistry
268
occur in the absence of air in a Pyrex tube support the suggestion that the primary process is an n -+ n* excitation producing a triplet excited state.llo The reaction pathway indicates that rotation about the C-P bond may be restricted by 0-C-P-0 conjugation in the excited state. The U.V. spectra of phosphorus hetero-aromatic compounds show marked similarities with the nitrogen analogues. The bands of the former usually occur at slightly longer wavelength. Thus the spectra of (124; X = P) and
(124; X = N) possess bands at 286 (log E 3.89) and 280 (log E 2.06) respectively,6 and the spectra of (125; X = P) and (125; X = N) possess two bands each at 328 (E 16,600) and 280 ( E 64,500), and 317 ( E 16,700) and 246 nm (E 79,500) respectively.l12 A comparison of the spectra of a wide range of para-substituted triarylbenzylidenephosphoranes (1 26) has shown that conjugation is interrupted by the phosphonium atom.lsa The auxochromic effect of the phosphonium centre in (127; X = Ar,P) was limited and remarkably
(126)
(127)
similar to the effect of nitrile or alkoxycarbonyl (127; X = CN or C02R). In contrast to this relatively weak effect there is a strong mesomeric interaction when the donor group acts through a benzene ring, e.g. (128; Z = CH, or NMe,). In fluorenylidenephosphoranes (129; R = alkyl or aryl) the substituent X has a small influence over the whole The effect is not comparable to the mesomeric interaction in planar pn conjugated systems. Br
(1 29) lS4 lss
G . P. Schiemenz, Communication at the 'Ylide Symposium', Leicester University, July 1970. H. Goetz and B. Klabuhn, Annalen, 1969, 724, 1 .
Physical Methods
269
An attempt has been made to identify, qualitatively, the nature of the .rr-interactions in (1 29) lS6 and in the di-co-ordinated phosphinimine (13O).ls6 The spectra of phosphorus ylides in which the carbanion is part of an extensive chromophoric system have been reviewed.lS7 The olefinic and hetero-aromatic derivatives of the Pv phosphorane (13 1)
possess more-intense absorptions in the 260-300 nm region than bisbiphenylenephosphonium bromide in accordance with the Pv atom being a better auxochrome than the PIv atom.114 Two overlapping sets of 'structured' bands at ca. 265 and 295 nm were attributed to different radial and apical Pv aryl interactions. The photoelectron spectra of phosphine and arsine have been determined and the ionisation potentials calculated.ls8 The electronic spectra of tertiary phosphine complexes continue to be of much interest.lE9 6 Rotation Optical rotation is used extensively in the stereochemical studies of PrlI and PIv compounds and recent work has extended the range to Pv and Pvl compounds. The configurations of triaryl- and trialkyl-phosphine oxides have been correlated by a series of stereospecific interconversions of menthyl phosphinates and phosphine Also, the absolute configuration of a series of phosphonium salts (132) has been established by 0.r.d. Salts Ph, PhHzCCpft
Me
/
B ~ -
Ph.
Me-'$-y /
Prn
(133) lS6
Ia8
lg0
IS1
B ~ -
Ph.
Me,'p-: Pr
/
(1 34)
H. Goetz and B. Klabuhn, Annalen, 1969, 724, 18. A. V. Dormael, Bull. SOC.chim. France, 1969, 2701. G. R. Branton, D. C. Frost, C. A. McDowell, and I. A. Stenhouse, Chem. Phys. Letters, 1970, 5 , 1. L. H. Pignolet, W. De W. Horrocks, and R. H. Holm, J . Amer. Chem. SOC.,1970, 92, 1855; G. J. Leigh and D. M. P. Mingos, J . Chem. SOC.( A ) , 1970, 587; E. C. Alyea and D. W. Meek, J. Amer. Chem. SOC.,1969,91, 5761. R. A. Lewis and K. Mislow, J . Amer. Chem. SOC.,1969, 91, 7009. W. D. Balzer, G e m . Ber., 1969, 102, 3546.
270
Organophosphorus Chemistry
with the configuration (132) or (133) have a large positive Cotton effect at ca. 220 nm. The salts (132) also have a negative Cotton effect at 250280 nm but the salts (133) vary in sign in this region. The corresponding ( + )-phosphines (1 34) have also been examined.lQ2 Trisbiphenyl-2,2'-diylphosphorus(v1) (1 35) can be separated into its enantiomers. Circular dichroism has shown that the (-)-isomer has the
(135) structure (1 35) which resembles a left-handed screw.lQ3The phosphorane (136) has been isolated in its d-, I-, and meso-form~.~~* The relationship between the magneto-optical or diamagnetic contributions and the -rr-characterof the P-0 bond has been improved,lQ5and has been studied, together with molar refraction, in some fluoro-alkoxy compounds (137; X = :) and (137; X = O).lU6The main magneto-optical
factors, such as ionic character and magnetic polarisability, for a fairly wide range of PI'' and corresponding PIv phosphoryl compounds have been studied.lQ7It was found that the magnetic rotation of the P-0 bond increases with the electronegativity of the P-substituents in the order R < C l < O R < F . The Ni-P bond of nickel chloride complexes has also been investigated.lQ8
7 Diffraction X-Ray diffraction of the aminodifluorophosphine (138) at - 110 "C shows the groups at nitrogen to be planar, with one methyl group eclipsed with L. Horner and W. D. Baker, Chem. Ber., 1969,102, 3542. D. Hellwinkel and S. F. Mason, J. Chem. SOC.( B ) , 1970, 640. lS4 J. Ferekh, J. F. Brazier, A. Munoz, and R. Wolf, Compt. rend., 1970, 270, C , 865. P. Castan, M. C. Labarre, and J. F. Labarre, J. Chim. phys., 1969, 66, 1652. lee D. Voigt, P. Swysen, and M. C. Labarre, Bull. SOC.chim. France, 1969, 3383. 19' P. Cassoux, P. Castan, P. Swysen, M. C. Labarre, and J. F. Labarre, J. Chim.phys., 1969, 66, 1770. Is* P. Cassoux and J. F. Labarre, J . Chim. phys., 1969, 66, 1420; J. M. Savariault, P. Cassoux, and J. F. Labarre, J. Chim. phys., 1970, 67, 235. lS2
lS3
27 1
Physical Methods j;P,
Me I
.I./N\Me
*I*,Cfi
'B
/
Ph
Ph
P
P
F/
/C
Ph/
'Ph
the phosphorus lone pair of The P-N bond length (163 pm) is much shorter than the sum of the covalent radii for P-N (178 pm) but similar to that for P=N (164 pm). Also, the PNC bond angle is just over 120". The stereochemistry has a bearing on n.m.r. studies (see Section 1D). A more refined structure determination of the diphosphineacetylene (139) shows that the lone pairs of electrons are at 90" and the P-C(sp) bond length is slightly shortened.200 One may ponder whether conjugation of the PrI1 atom with different acetylenic r-bonds is responsible for the stereochemistry. The major isomer of the phosphetan (140) is trans and not cis.24 In previous work, the crystals of superior form, which were selected for study, turned out to be those of the minor component. The phosphole dimer (141)
has a more strained CPC bond at the bridge (87")than the CPC bond in the endo-fused ring.2o1 The accuracy of the structure determination was considerably improved by cooling to -40 "C. In six-membered rings, e.g. (142) 202 and (143),203the CPC bond angles (104"and 102"respectively) are similar to the OPC angles of dioxaphosphorins. In (143) the bond angles involving sulphur are increased from tetrahedral up to 116". This is attributed to the large sulphur atom being relatively close (195 am) to the
E. D. Morris and C. E. Nordman, Inorg. Chem., 1969, 8, 1673. J. C . J. Bart, Acta Cryst., 1969, 25B,489. 201 Y . H. Chiu and W. N. Lipscomb, J. Amer. Chem. Soc., 1969, 91, 4150. 2 0 2 IMazhar-ul-Haque, J . Chem. SOC.(B), 1970, 711. 2 o s J. D. Lee and G. W. Goodacre, Acta Cryst., 1970, 26B,507. lB8
2oo
272
Organophosphorus Chemistry
phosphorus atom. The intermolecular P.. , ...S distance (347 pm) is also small and provides additional evidence that the van der Waal's radius of sulphur should be less than the Pauling (1960) value of 185 pm. Even accepting the suggested smaller value of 172 prn and adding this to the 190pm radius for phosphorus, the contact is still short. Decreasing the ring size to five-membered, as in (144), has surprisingly little effect on the P-P and P=S bond length^.^^^ A similar P=S bond length occurs in (145).205
(1 44)
(1 45)
X-Ray diffraction studies on the phosphinimine (146) 206 show that the PNC bond angle is 119" in accordance with an sp2-hybridisednitrogen. The dihedral angle (55-3") between the methyl and phenyl groups [see (147)] does not correspond to the most staggered conformer, cf. methylenetriphenylphosphorane (148).207The P-N bond in (146) (164 pm) is almost as long as in methylenephosphoranes and somewhat longer than expected; F
H
Ph
P Ph,P -N
+ -
N-PPh, N (149)
note, the P-N bond is 153 pm in (149).,08 Electronegative substituents generally tend to lengthen the remaining bonds to an atom, but the P-N bond is usually an exception because electron withdrawal from phosphorus promotes v-bonding and shortens the P-N bond, e.g. 160 for (Me,PH),, 157 for (Cl,PN),, and 151 pm for (F,PN)4.209It is possible that in (146) P-F n-bonding is competing with P-N rr-bonding. 204 205
206
207
208 209
J. D. Lee and G. W. Goodacre, Acta Cryst., 1969, 25B,2127. J. D. Lee, G. W. Goodacre, S. C. Peake, M. Fild, and R. Schmutzler, Naturwiss., 1970, 57, 195. G. W. Adamson and J. C. J. Bart, Chem. Comm., 1969, 1036. J. C. J. Bart, J. Chern. SOC.(B), 1969, 350. T. S. Cameron and C. K. Prout, J. Chem. SOC.(C), 1969, 2281. A. W. Schlueter and R. A. Jacobson, J . Chem. SOC.( A ) , 1968, 2317.
Physical Methods
273
The phosphinimine (149) is rather interesting because the crowding round the central phenyl ring prevents the nitro-groups from conjugating with the ring.208Delocalisation of the negative charge into the central ring will also be limited by the presence of three such groups on the ring, consequently the P-N bond length of 153 pm is probably the result of considerable back-bonding to phosphorus. The reaction of triphenylphosphine and benzotrifuroxan also produced several other interesting compounds.210In the stabilised phosphinimine (150) the P-N bond (163 pm) is lengthened because the negative charge is extensively delocalised by the nitroso-group.211 Notable is the way in which the electron-rich oxygen atom turns away from the phosphonium centre, avoiding what would appear to be a stable six-membered ring incorporating an ionic bond. Possibly such P+...O- bonding would require the phosphorus atom to possess considerable trigonal-bipyramidal geometry, which in turn would require the nitrogen and oxygen atoms (for reason of bond angles) to occupy unfavourable radial orientations. \When the phosphorus and oxygen atoms are separated by two atoms the electrostatic attraction may be appreciable because in (151) they are only 301 pm apart.212 The P-Cbond length (177 pm) is almost as long as the P-C (phenyl) bonds (179-0
9,
’0,