The Chemistry of Heterocyclic Compounds, Imidazole and Its Derivatives

I M I DAZ 0 L E and Its Derivatives Part I

KLAUS HOFMANN Professor of Biochemistry, iltediccrl School, Unilrersity of Pithtncrgh

1 9 5 3

INTERSCIENCE PUBLISHERS, INC., NEW YORK INTERSCIENCE PUBLISHERS LTD., LONDON

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IMIDAZOLE and Its Derivatives Part I

This is the sixth volume publiskd i n the sm*es THE CHEMISI'RY OF HETEROCYCLIC COMPOUNDS

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THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS A SERIES OF MONOGIlAPHS

ARNOLD WEISSBERGER, Consultiny Iid,ilor

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I M I DAZ 0 L E and Its Derivatives Part I

KLAUS HOFMANN Professor of Biochemistry, iltediccrl School, Unilrersity of Pithtncrgh

1 9 5 3

INTERSCIENCE PUBLISHERS, INC., NEW YORK INTERSCIENCE PUBLISHERS LTD., LONDON

LTBRARY OF CONGRESS CATALOG CARD NUMBER &3-7158

ALL RIGHT8 RWERVED. Thie book or any part thereof must not Iw reproduced without prmiesion of the puhlhher in writing. Thia applies epecifically to phohtat and microfilm reproductions.

INTIZRBCIENCE PUBLISHEIS, INC., 250 Fifth Avonue, New York 1, N. Y. For ( 3 r d Britain and N o r t h Irelad: Interscience Publiehers L a , London ISBN 0-470-37653-8 ISBN 13: 978-0-47037653-9

This book is dedicated to the memory of FRANK LEE PYMAN

a pioneer in imidawle chemistry

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The Chemistry of Heterocyclic Compounds The chemistry of heterocyclic compounds is one of the most complex branches of organic chemistry. It is equally interesting for ita t-heoretical implications, for the diversity of its synthetic procedures, and for the physiological and industrial significance of heterocyclic compounds. A field of such importance and intrinsic difficulty should be made as readily accessible as possible, and trhelack of a modern detailed and comprehensive presentation of heterocyclic chemistry is t.herefore keenly felt. It is the int.ention of the present serics to fill this gap by expert presentations of the various branches of heterocyclic chemistry. The subdivisions have been designed to cover the ficld in its cntirety by monographs which reflect the importance and the interrelations of the various compounds, and accommodate the specific interests of the authom.

Research Laborcrtories Eastman Kodak Cornpang Rocheater, New York

ARNOLD WEISSBERGER

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Preface /micluZole and Zls Deririatitres (Part I ) summarizes the chemistry of thc, imidasoles, imidazolines, imidszolidinm, aid benzimidszoles and their s Derivatives,” preents derivatives. Section 1, “Chemistry of C I ~ s e and a critical evaluation of the synthetic methods, and the fundamental physical and chemical aspects of these compounds. Brief descriptions of the pharmacological properties of some of the biochemically important derivatives are also included. Section 2, “Systematic Survey and Bibliography, ” contaim a comprehensive noncritical surrey of the pertinent literature. Names, melting points, melting points of some derivatives, and i ~ y a r s 1919 to 1950. literature references are given. The survey ~ * o v ethe Substances that were prepared before 1919 and were not mentioned in the literature covered are not listed ; Beilsteh’s H a d ~ 6 C should h be consulted for informationabout these compouuds. The subject is treated hi this fashiou with the iiiteiktion of preseiiting a readable account of the fiindamentuls, yet ut the same time attempting a comprehensive coverage of the entire field. With but few exceptions the original articles have served a~ the source. The Chemical Abstracts reference is listed, in addition to the primary reference, for any article not consulted in the original. In some instances, data from the older literature have been reevaluated in the light of more recent concepts, and a number of reaction mechanisms are tentatively presented. Most of these interpretations are based on analogies with better understood examples, and must remain qeculative until quantitative information is forthcoming; they are given with the aim of stimulating inquiry into the theoretical aspects of imidaeole chemistry. Many friends and colleagues have aided in the preparation of the book, and the author is greatly indebted to them. Miss Anne Bridgwater abstracted the literature for the compound tables and organized Section 2. Dr. R. S. Tipaon read the entire manuscript slid made many valuable suggestions. My sincere thanks are also due to Drs. M.F. Dull and 8. 11. Sax,and Mr. F. Tausig for their help in checking literature references, and for reading tlw proofs. Pittsburgh,.Pennsylvania May, 1953

K.H.

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Contents l’mfwe .................................................................

ix

Section f

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CHEMZSTRY OF CLASSES AND DERIVATIVES

I General Properties and Structure of the Imldezoles. . . . . . . . . . . . . . . . . . .

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A Somenclat.uro. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .......... 1% Physical Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Boiling and 3lcltirig Points . . . . . . . . . . . . . . . . 3 Solubility ............................... 4. Molecular Weight nncl Dnprrc of .4.s~wintion 5. V i o s i t y . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Dipole bfonionts. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. ... . . 7 Spwtrascopic Propcrtien . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (x) Ultravinlrt AlwqBtinii Spwtrn . . . . . . . . . . . . . . . . . . . . . . . . . . [b) Ramarr Spectra.. . . . . . . . .......................... (c) Clicmilumiiiesi.ciicc!..... 8 Micrcn?lluncousPhgsind Prnpwt.ics. . . . . . . . C. Chomical Propcrticn ......................... 1. Basic Strength . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Pneutioricirlic Character . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 C%cmical StRldity arid r\mmat.ic!Charnctcr . . . . . . . . . . . D. St.iuctural Considcmtions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I . The C!la&cd Iiniclnnolc Forinu1.r . . . . . . . . . . . . . . ......... ...................................... 2 Currcnt Vims .... E. Tautomcrio Charrictcr . . . . . . . . . . . . ..................

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10 10 11

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XI The Alkyl- and hrylimidazoles. . . . . . . . . . . . . . . . .

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3

5 5 5 7

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3

. ........ . 3. The Wcidcmhagon Synthmis .......... . . . . . . . . . . . . . . . . . . . . . . .

4 Formation from Carbohydrates ..............................

5. Formation from Z ( ~ ~ ~ n i i d a e o I a t h i o and n e s Mthiohylnntoiiiina . . G Formation from I m i d a z o l ~ h o x y l i cAoi& .............. i Formrrtion from PImidrnolinetl . . . . . . . . . . .............. 8 ~ i s c c ~ l a n wPrWdurccr us ..... .............. I3. Properties and Chemical Behavior. . . . . . .................... 1. Gcncnl Propcrtirs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 2. Acylation . . . . . . . . . . . . . . . . . . . .................... 3. Alkyhtion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

xi

11

11 11 13 13 13 15 16

li 17

19

20

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.4 Syiit.hot.ic P r w d u r m . . . . . . . . . . . . . . . . . . . . . . . 1 Intmluction . . . . . . . . . . . . . . . . . . . . . . . . . 2 Tlw Rrwbi.szcwski Syntliesis . . . . . . . . . . . . . . . .

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c

33

38

39 41 42 42 43 45 46 47 40

sii

C~OlltelltR

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111 The 0x0- and Iiydroryimidamles and Their Sulfur Ailalugues . . . . . . .

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.4 The Oxoimidasalrs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Imicisral~~rl~os.~lilt~li~tl~.s ... . . . . . 2 Imidxmlc?Kctriiicw . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . 3. Imidazolo~tt+s and Tliioiicbs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

(a) Nomenclature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

(I> Structural ) Coneitlerations Itt.lgtrdiiigthe 2(3H)-Iniid:izalon~~ and Thionca.... ...................... (c) 2(3H)-Iniid:ixola . (d) 2(3H)-Itiiidt~zn1c ( 0 ) 2(.H)-Iaiiclrrzolono~ . . . . . . . . . . . . . . . . . . . . . . . . . . . . ( f ) 4(5H) (or S(4H))-Imitl:txoloiii~~ . . . . . . . . . . . . . . . ;. . . J3 . The I I y ~ x y . z l k y l i n i i c ~ s n..... lt~. ... . . . . . . . . . . 1 ..onoliydrosyrtlkpliniirl.sal. .......................... (a) lIydrosymetliylitiiidazciIcn. . . . . . . . . . . . . . . . . . . . . . (I)) 4(or 5)-(2-H~ilroxycttiyl)I1iii~.i~til~ . . . . . . . . . . . . . .

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2. I’olyh~drox3~alkylimid.o1~.. . . . . . . . . . . . . . . . . . . . . . . (a) -#(or6)-Polyliycl~sy.~lkyliniict~olc~~ . . . . . . . . . . . . . (I)) l-Pol~~h~~.rospnlkgliinitlneolcg .....................

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IV The Haloaenoimidazoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A . 13romoimi&zoles..... ......................................

. ..................................... 2. Propert.ies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 I’repnrrrtive Met

. . .

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l3 Chloroiinidazoles.... ..................... C Chloroalkylimidaroles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1) Imloimidazoles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Preparative Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Propertit*s.................................................

V The Nitro.. Arylazo.. and Aminoimidazoles ..........................

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A Xitroimiilssoles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Synthetic Mctliocls a i d Orientation of the Xitro Croup . . . . . . . . . 2 Properties. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . R Arylneoimidazolw 1 Formtion and Orientation of the A r y h Group . . . . . . . . . . . . . . . 2 Application 01the Diazo Twt to the Identification and Ihtimnt.ion of Imiclasoles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Pmpertiw . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C AminoimidR7,olm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 2-Aminaimidrzalcs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 4(ar 5)-Aminoimidazolrs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . L) lfistamine . . . . . . . . . . . . . . . . . ........................ 1 Discovery, Distrilmtion ature, and l%armscologiral Effects. . 2 Isolation from Natural Jfatorials ....... 3 Quantitative Ehtimation of Ifstaminc . . (a) Biological Methods ........................... (b) Colorimetric Methods ........................... 4 Formation by Microorganisms...............................

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Ill 111

111 117 119

121

122

In 123

127 121

127 131 136 136

139 139 141

141 142 143

I43 145 146 146

147 149

\I: The Nitro.. Arylazo.. and Aminolmidazolea (continuad)

. 7. Structural Analogues of Hi&aniino

5 Preparative Methods ........................................

6. Physical and Chomical l’iopwtic6. . . . . . . . . . . . . . . . . . . . . . . . . . . .

........................... Position Isomers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (1)) Ring-SulBtitution Products . . . . . . . . . . . . . . . . . . . . . . . . . . . ( e ) :V->fonoalkyl- niid :V-Dialkylliistamine Derivativts. . . . . . . (ti) lliitamine Annlogues Yoerming Iqge? or Shorter Aliphatic Side [?hain8 .......................................... 8. Pharrnndogicd Specificity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (ti)

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VI The Imidazolecarboxylic and Sulfonlc Adds. . . . . . . . .

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158 158 160 163

lfM 16.5

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A . Tinitla~ok!carl~xylic Aeicb . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. l-Imidn.~olecr~r~~osylic heidtj. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 ZIrniclnsolecnrlmsylic Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 4(or 5)-Iini~zolccarboxJ.iicAcids. . . . . . . . . . . . . . . . . . . . . . . . . . 4 4,~Imiclnxoleclirnrk~s~lic Acids . . . . . . . . .................. 5. 4(or 5)-tirnino-j(or 4)-Irnidazolecurl~oxylic Acids . . . . . . . . . . . . . (a) Occurrence nnd J f e t k r d of Prcpnrrrtion . . . . . . . . . . . . . . . . (l ), Coiivetuioii into I’uriiies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . G JIistidine .................... ......................... (a) Discovery. l)i&ril)utioii it .It.UI‘C, autl Sttuctulr? . . . . . . . . . 0))Noniencl;rt.~iu.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (c) Isolation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (cl) Qunrrtitntive Estitn.rtioii . . . . . . . . . . . . . . . (e) Synthesis rnid Rcsolutioii . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (f) Pli.y&ul and Chemical Yrolwbics . . . . . . . . . . . . . . . . . . . (g) Structural Anrilogues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 Iniiclatolwulfonic Aci& ............................... I Structural Cowiden ................................ 2. 1-Imidwolesulfonic .4ck 1s. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 ZIrnidszolerrulforiic:Acids . . . . ..... ............... 4 4(or 5)-Imid~xolt~ulfo1iic Acids . . . . . . . . . . . . . . .....

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150 153

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.Inoimidazolldlnes,and Imidazolidinen ............................

1’11 The Imidazolinee, 2-Imidazolidonee. 2-1midazolidinethiones, 2-Im-

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175 175 176 176

178 179 179 182 184

181

188

188 194 197

203 206 206 206 200

207 213

A Komenclnture . . . . . . . . . ..... ......................... 213 U 2-lmidnrolines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213 1. Synthetic Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213 2. General Properties and Structural eneideratioiis . . . . . . . . . . . . . . 219 3. Acylat.ion ................................................ 221 1. Alkyhtion . . . . . . . . . . .............................. 223

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5 Prwtical Applications

rnincologioul Actioii

C. ZIiiiiclnxolidories .................................................

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1 Syritfietic Methods and Prolwrtirs. . . . . . . . . . . . . . . . . . . . . . . . 2 Ikxthioliiotin s i d Its k i l o g i e x . . . . . . . . . . . . . . . . . . . . . . 1) ZIiiiidslcolitliii.tIiion.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . E ZImiiioiiiii.zolitIi~i. ...........................................

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. F. frnitlrtxolitliiiw. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

226

2x 231

234

238

242

XiV

Contents

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VIII The Bemimidamlea.............................................. 247 A Nomenclature. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.47 B GeneralPrope-rties ........................................... 1 Boiling Points. Melting Points. and Dcgrw of &mi&.n ... 2. Pmdouoidic Character..................................... 249 3. Basic Strength and Eleotmnic Structure ........ 4 Ultraviolet Absorption Spectra . . . . . . . . . . . . . . . . 5. Chemical Proporties ........................................ 254 6. Tautomeric Clitinwter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255 C. Synthetic Proodurer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . 258 2 Formation fmni Acyl: . . . . . . . . . . . . . . . . 258 3. Formntion from ~ ~ I i t t r ~ y l e r i t ~ l i ::nit1 i ~ i ~C:irl)osylic i i i ~ ~ ~ Acids, Avid Anhydrides, Esters. or Amidw ............................... 200 4 . Formation [rum o-l’henyleneclinrnincs and h’it.r.ihw.. . . . . . . . . . . . . 2625 6. Formation fmni o-Phcnylent~cliamii~crc niid Iiiiiiio 1l;tJvtrrc o r I n i i i i o Tliiouthers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280 0. Fornlcrtiou from o-Plienyle~ieclia~iii~~e~ autl AIdt41ycIc~or Kcttoricw . 267 7 Miscellaneous Procedures................................... 211 D. Tlro 1-AcS.lbeaziniiiluzolen irnd the BuJiilwrgerIlc:rcl.iori . . . . . . . . . . . . . . 273 E . The Alliyl- ant1 Aryllm~izimi~Lazoles and 1.3-Dialkyll~c.i1siiiii1Itrzcrliui1i Salts........................................................... 276 F. The 0x0- aud EiydrosylJe~inii~zolcn :nit1 Their Sulfur A ~ i : t I o ~ i i i : ~ 1. “Osunhylro Baw!~” ar “Ox~~crixiniicltrxol~“ .............. 2 2(3H)-Benzimiduzolones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285 3. 2(3H)-13etuimidazolethion.. ................................. 291 4 . 1IJdrusy~rllrylbet.i.iid.oleN ................................. 293 (:L) I-(l)olyhydro~yalkyI)berlziriiill:~i)l~~ (I-ClycosylLeuiiIlidusoles) ............................................... 293 (b) Z(Moiioli~O.clroxyalb;yl)l~enzimi~zolc. . . . . . . . . . . . . . . . . . . . 296

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Z(Altlo~~lyl~ydrosyt~lky~)l~c~nsi~d~zolt?rr .... ((1) Altlnrodiiiensimida ole.. . . . . . . . . . . . . . . . . . . (i Tlic I I t d o ~ ~ i ol ~ i ei n~ i da~ ...... ol es . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. ..-Iklogenobensimida.o.e. ................................. 2. 2-Chloroknzirni&zoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. U=hlomnlkylbcnzimi~asole..... ......... I1. The Nitro- and Anlinobeiidmidnzolcs. ................ 1. Nittdmwimidnzoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Aminohenaimidazolcs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (a) Bz-Aminobeneimidazoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (11) ZArninobeneimidaaoles. . . . . . ................. (c) Aminoayl- and Arninoar.li~i.irziiiii.zoie. ............... I. TIIOJ3enziniidazolecarbo~licand Sulforiic Acids. . . . . . . . . . . . . . . . . . . . 1 Carboxylic Acids ................................ 2 Sulfonic Acids ............................................. (c)

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300 300 302 303 304 304 308

308

309 310

313 317

Section 2. SYSTEMATIC SURVEY AND BIBLIOGRAPHY Key to Al)l)rc:vicit.ionw.. . . . . . . . . . .

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. . . . . . . . . . . . . . . . . . . . . . . . . 326

I. Imidazoles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . 327

A. Alkyl- r ~ i i t lArylinridrzol(%.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327 . . . . . . . . 330 13. Alkyl- and Arylimiclncolium Sii1t.s. . . . . . . . . . . . . . . . . . . C. 0x0- and Hydrosyimidamlos and Their Sulfur 1. 2(3H)-Imidazoloncs. . . . . . . . . . . . . . . . . . (a) Alkyl- nml Ar~l-2(3H)-imici~olones.. .. . . (I))0s-, I.lvdrosynlkyl-, RIKI Hydrosy (c) I~lalognriortlkyl-,Aniinonlkyl-, and Sulfoalk~E.2(3H)-imiclnzolonw. .. . .. ... . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331 ((1) 2(3H)-Imid~~IoiicrarI ~osylicAcids. . . . . . . . . . . . . . . . . . . . . . 332 (e) Cnrhsyrlkyl- and ~arhos~.nryl-2(3H)-in~itIa~olo1i~. . . . . . . 332 (f) C h t ~ ~ x rmcl y - Cnrbo~yalkyl-2(3H)-irnidasoloncsContnining Additions1 Functional Croups. . . . . . . . 2. 5(4H)-Imidazolonos. . . . . . . . . . . . . . . . . . . . . 3. 4(5H) (or 5(4H))-Imid~~obtios. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334 4. 2 ( 3 H ) - I m i c l n s ~ ~ t h i(ZXlerclrrptoin~iclr~~olc.~). o~i~ . . . . . . . . . . . . . . . 336 (a) Alkyl- and Ar3’1-2(.7H)-imiditxol~thialrc.a.. . . . . . . . . . . . . . . . 336 (la) 2(3H)-Imitl~olcthicmc.sContaining AdcIit.icmi1 Ihiic.t.iorial Grou............................................... 337 ( 0 ) 2(3H)-In~idao;ol~t.hioncxnrl~s~lic ~ n t lCarl)osya.lkyl-

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.

2(3H)-imidaeolethiori~s.. . . . . . . .

. . . . . . . . . . . . . . . . . . 388

. . . . . . . . . . . . .. . . , . 339 .i 4(5H) . (or 5(4A))-Imidasolethionc,s. . . . 6. Mono- and Polyhydroxyalkyl- and J r y t l m s ~ n r ~ l i m i ~ l ~ o l ~ , Their Ethers and Halogeno Derivativr?.. . . . . . . . . . . . . . . . . . . . . . 340 7. Mercaptoalkyl- and Mercaptoarylimida7alcs.. . . . . . . . . . . . . . . . . . 341

8. Imidaeolecarhoxaldehydcs and Ketones. . . . . . . . . . . D. Halogenoimidssoles.. .. . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . 1. Hdogcno-, Halogenmlkyl-, and Walogenoarylimidazoles. . . . 2. Halogenated 61ks.I- and Arylimidazolium Salts.. . . . . . . . . . E. Nitroimidazoks.. . .. . .. ..... .. . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . , . . 1. Nitro- and Nit.mnrylimidaaoles. . . .. . 2. Nitwlkyl- anti Nitroarylimidn7mlc~ tional Groupv.. . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Nitroalkyl- and Nitroarylimidamlium Salts. . . . . . . . . . . . . . . . . . . F. Arylazoimidaeoles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... C . Aminoimidades. . . . 1. Amino-, .4minonlkgl-, and Aminoarylimidazoles. . . . . . . . . . . . . . . . 2. Amino-, Aminoalkyl-, and Aminoarylimidazoles C a n t h i n g Additional Functional Groups.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . , . i t Cyano- and Isocyamtoimidaxdcs. . . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . .

.

342 345

346 346 347

350 361

I . I midazoler (cordinmi) . .

.

1 TinidsxciIrrtlrrt~sylic ht.itla . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 . %Ioiitwirrlxxylic Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . bi) .itkg1- ant1 A ~ l i n i i t 1 : i x a l ~ : r r l ~ ~Acitls ylic . . . . . . . . . . . . . (13) Imidazolecrrrl>oxylic AaicLs Containing kldit.ianltl Fu tional Groups ........................................ (c) Carboxyalkyl- awl C ~ r r b o s ~ a r y l i m i d xIncluding ol~~ Those Containing .4 dditional Functional Grnirps . . . . . . . . . . . . . . . . (1) r&iat.idiiic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (2) i ~Cisticline l ................................ (3) oirHist.idiiic. . . . . . . . . . . . . . . . . . ............. (4) HiRtidiiie PcptidrR . . . . . . . . . . . . . . . . . . . . . 2 Dicarboyylic Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (a) Alkyl- and .4r~limiclrrsol~?clicnrl.s~lic! .\cidx . . . . . . . . . . . . . . (1)) Imidazalociiaarhos~lic Acids Cnnt..thing Acitlit.ioii:rl F’urtctianal Croup ......................................... (c) C a r b o x ~ : ~ l k y l i m i d ~ s o l ~ n ~ ~Aeitl~ o s ~ l i cIlielutlirig Those C h i t h i n g Aclditicmsl Functionnl Grnups. . . . . . . . . . . . . . . . J 1micl:raoleuulfinic slid Sulfoiiie .4rids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I< Imidmolo Arscnicale. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I Isoimitiazolcs....... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 I Iek!rnring-Sul)Rtit.utcll ImitLi7xhs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Funin 1hivat.ivm. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Tlric~plieiic? Ihriv:rt.ivt*s.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Tliirrxolr Ihriv:tt.ivtw. .......................... 4 Pyridiiic hrivntivw . ............................... 3 Pilinritliiic~Dt~riv:rtivt~s . . . . . . . . . . . . . . . . . . . . . . . . . 6 Morphnliiw Dc-riv.rtivcs. . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 l’yriniitliiic 1)t.riv:i.tivt-s. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Quiriolinc 1h~riv.itivw. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Acritliiio Dc?riv.rtivt!s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Y I3i- mtl I%iinimiciaxoltw ... ..............................

.

.

. .

..

.

. .

. . . . .

.

.

.

I1 Imidazolines..............

.

.......

.....

.

352

3.53 355 358 358 359

360 361

362 363 363 363 3(W

3rd 364 364

364

36.;

3115 3% 36 3(15

366 367

A 2-Tmid.i.soli~ic ..s .................... ....................... Mi 1 Alkyl- :ind Aryl-2......................... 3f11 2 :\lkyC ant1 Aryli:nitl:~soli~iiuni Brlk ........................... 360 3 Alkyl- :riitl Aryl-2-imicI.w~linw(hnttrining Achlitiniial Piiric.tioiinl

. . . orivnt.ivrR.. . . . . . . . . . . . . . . . . 5 . Piperitliiiti Dttrivntive. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Thianeplithetic I)t.rivativcn . . . . . . . . . . . . . . . . . . . . . . IC 3% ant1 Di-%imitlasolinrs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

.

.

aao

371 372 372 372 352

372 358

373 3 3

CoiiknLs

.

xvii

I11 ImidazoUdines. ....................................................

.\.

Alkyl- and Ar?.liriiidnnolidint.x.....................................

. Yittivt itmil( hwtps C . HekmrinpSulwtJ tuttwl Imidazoliclincn . . . . . . . . . . . . . . .: . . . . . . . . . . . . . . 1. F u n n h r i v n t i w s .............................................. 2. Triazole hrivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D. Biaimidazolidines................................................ IV. Imidamlidones. Imidazolidlnethiones. and 2-Jminoimidazolidines.. 1% Alkyl- 1 ~ l i t 1Ar?.liniid,r7~lifli1i~~ Chit:iitiiiiK Atltlit i o t i : ~I

.

.\ 2-Imidazoliclones (Ethylcneurcas) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Alkyl- and Aryl-Zimidardidonea .............................. 2. Alkyl- and Aryl-2-imidazolidones Containing Additionn1 Functionnl Gmups .............................................. 3. ZImi~lnrolidonec~rhoxylicAcids and Carboxynlkyl-Zimictseolicbnw Including Those Containing Additional Functional Gmups . 13. 4 and 5-Imitlasoliclones.......................................... C. 2-Imidazolidinethiow (Ethylenethioureas) . . . . . . . . . . . . . . . . . . . . . . . . D. 4Imi(Jszolidinethiones ........................................... E. 2-11nitioimiclazolitIi~ies(Ethylenegunnidinm)........................

V Benzimidamlea .....................................................

. . .

. .

37.3 353 Xi4

37.5 355

375 316 356

376

31g

376 377 378

378 379 379

379

A Alkyl- and Arylhonzimidazolea. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379 13 AlkyE and Arylbenzimidazoliuni Salts ............................. 382 C Oso- and HyclroxyhenzimidRzolcs and Their Sulfur Analogucw ......... 382 1 2(3H)-Benzimidazoloncs (ZII~dros~I~.xiaimids~oles, o-Phenylene-

.

UlWbS) .................................................... 382 (a) hlkyl-2(3H)-l~ciiziinicl~zolonr~ Iiiclucling Those Containing Ackiitioiinl Functional Cmups .......................... 382 (11) 2(3H)-Benzimiclaaolon~a~~os~lic Acids sntl Cnrhosyalkyl............................... 2(3H)-f~nzimida~olon~~ 3&7 2. 2(3H)-Benzimidseolet.hionw (ZJicrcnl,to.erizimiLnzol.. o-Phenylenetliioun) ...................................... 383 3. Monw and Polyhydrosyalkyl- and ~I~clro~~ar~1Iieiiximitlnzolcs, Their Ethers and Halogen Derivatives ........................ 384 (a) Hydroxy-. Irydroxyalkyl-. and H~~droxgnr~~ll~enzi~d.olea, Their Ethers and Sulfur Analngues...................... (I)) Hydroxy-. Hydroxydkyl-. and H y c l ~ . ~ ~ n r y l b c ~ i r n i ~ ~ z o l ~ Cantaining Halogen ................................... 386 (c) Polyhydnxyalkylbonaimidazoles........................ 386 4 Benzimidazolecsrbo?uIlde.d.s. Iietones. and Quiiionctcr . . . . . . . . . 381 D Halogeno-. Halogenoalkyl-. and Hal~norrrJ.ll~e~imiclazole~. ......... 388 I3 Nitro-. Kitroalkyl-. and Nitroarylhenzimidaznlea Including T h m Containing Additional Funct.ionnl Croups ............................ 388 F Aminobeneimidarol............................................. 389 1. Amino-. Aminodkyl-. sncl .eninoalrlI.nrirni~ a.oles. . . . . . . . . . . 389 2 Amino-. Aminoalkyl-. and Aminoar~~lhensimidarol~ Containing Additional Functional Croups............................... 392 394 G Cyanohenzimidazol.............................................

. . .

.

.

.

sviii

.

\? Ikrisimidaxolt-s( w n h t t c d )

11. H ~ ~ i i z i t ~ ~ i t l : t . ~ o I ~At-ids r b ~ s ~ l i i. :. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 . \lonwri.rbosylic

AcMi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . :rncl A r ~ l l ~ c : ~ i s i i i ~ i t h s o l ~ At:idn ~ ~ r l ~ Iitcludinr s~li~! Thorn Containing klditiond Functional Croups . . . . . . . . . . (b) Carbosyrlkyl-, C:rrrlxwydkxnyl-, and (:rrrl,os\.sr?rlltcrtximiClazolcs..... .......................... 395 2. Dicarhoxylir. :\(.ids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397 I IJrtrximidunolc~ulfonicAcids, Sulfn.ilkyl-, and Sulfortl.3.lbeiIziniicfRzolc~s. 398 J . l~ndmidnrolcAmtiia.ils ..................... . . . . . . . . . . . . . . . . . 398 li. 2.3-Mhydmlw~iraimitlrmolc.s( l ~ ~ ~ ~ i ~ i n i i c l ~. ~. ~ t l. i. i.i.~. ~. .s .) . . . . . . . . . 399 1.. 1 Ictcmrin~-~iih.sf.ittiirvl Ik?nximiclszoli*s ............................ 399 I . 1hir:in 1hriv:it iws . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3w 2. Tlriojihciic I )c*riv:iiivc.?c . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399 3. I’yrrolc 1)rriv:rt.ivc.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399 .b 1’yr:ixoltr I)criv.iiivi.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3w A . Iiyriiliiic! I)c!riv.it.ivia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . -100 t i l’i~~~*rieli~ic I>c*riv:it ivw . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 400 i. > forplioliI tc 1hriv:it iw!: . . . . . . . . . . . . . . . . . . 400 X . S:irithyl Dc1riv:i.iivc.s.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . MO 9. 1 ’ l r t l ~ : t I i ~ l f)i*riv:ti ~~ ivv . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 400 10. 1iril:crin :nit1 Irtclolo I )e!riv:it.ivcr.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . m 1 1. Quiniiliitc 1)c.riv:i.t.ivc.s.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 400 12 Ik.iiacnli:isc~ijiiti! 1hiv.it.ivc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 400 13. h c ~ t ! i i : ~ ~ i J ~ f 1hiriv:rt . I i ~ ~ ~ i ivc ~ ~ .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401 11 Hi-? IX-,: ~ i i c lI.ixl~criaiinicI.ize.lr.. . . . . . . . . . . . . . . . . . . . . . . . . . -101 (8)Alkyl-

.

.

.

. .

8

.

Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

401

Suhject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

421

SECTION 1 Chemistry of Classes and Derivatives

This Page Intentionally Left Blank

..

CHAPTER I

General Properties and Structure of the Im idazoles A. Nomenclature

This book deals with the chemidry of the ring system depicted below wliich has been designated as glyoxaline, imidazole, iminazole, or 1,3diazole by various workers. As a starting point for the following discussion it is essential to sct forth the rules whicli govern the naming and numbering of this ring system. Debus ( l ) ,tile discoverer of tlie parcnt compound, prepared it from glyoxal and ammonia and, to indicate its source, proposed the name glyoxaline. This name is still uscd in thc modern literature, especially by British workers. The name imidazole, uscd in the dresent monograph, is due to Hantzseh (2). He classified as azoles the five-membered p l y heteroatomic ring systems containing at least one tertiary nitrogen. The term imidazole implies a five-membered, heterocyclic ring system containing, in addition to a tertiary nitrogen, an imino group; just 8s the names oxazole, and thiazole designate five-membered ring systems containing in addition to a tertiary nitrogen an oxygen or sulfur atom.

The correct numbering of the imidazole ring is shown above. The imino nitrogen receives position 1, and the numbering follows around the ring so as to assign the smallest. possible number to the tertiary nitrogen, which is designated as position 3. The substituted nitrogen represents the starting point, for the numbering of the N-substitiited imidazoles. The designation of a substituent in position 2 offers no problem because of the symmetrical location with respect to the nitropens. The naming be-

:;

Chemistry of Classes and ncrivfitivrs

4

soiiieahnt more coniplcx, Iiowcvcr, wlicii a subst itirent is introduced in(o the 4- or 5-pasitioa. Depending iipoii tho position of t h iinino Iiydrogcn such A cu~iipoi~ncl must bc clcsigndcd as cithcr a 4- or H 5-nionosubstitntcd jniidszole, thc tautomoric cliatactcr of the imidazoles (see Section WJWS

E) precluding :t definite assignincnt of structurc. Such compounds are designated as 4 (or 5) -monosubstitutcd imidszoles.

k A siniilar situation exist.s in tlic case of the 4- and 5-disiibstituted and the more highly substituted iniidazoles. The following examples will serve to illustrate this point.

-

4 (or 5)-Methyl-5(or I)-ethylimidasole

H I

H

H

H

I H

2,4(or 2,5)-Dimethyliniidazole

H 2-Meth yl-4(or~)-ethylimi&~zole

A

2,4 (or P,5)-Dlmethyl-5 (or 4J-nitroiniidadc

Substitution of the iinino hydrogen eliininates the possibility of tautomerisni, and ct definite assignment of structure becomes possible, as illustrated below.

1,4-Dimethylimidnzole

1,S-DirnethyIimidamle

The sclieine outlined here will be used systeinatically throughout tliir monograph. Additional remarks regarding the naining of certain special types of imidazolcs will be found in the respectkc sections. The nomenclature used conforms to the rulcs of Chetr~icalAbstracts.

B. Physical Properties 1. Introduction

The consideration of structurc inust be based on physical as well 8s chemical properties. It thus seems logical to summarize first the physical properties of tlie iniidazoles. Whenever possible, tliis will be donc from tlie point of view of coinparison, since pertinent inforination on other hctcrocyclic, ring systems will :tit1 in 1inderst:mding tlie iinitlazole problem. 2. h i l i n e and Melting Points

'l'.ABLE I. Boiling Points of s Numhr of Five-Membcred Heterocyclic Compounds B.p., OC. (760 mm.)

Compound

-__

Furan ......................................... 32 Pyrrole ....................................... 131 Pymzole ...................................... 187 1,2,3-Triazole .................................. 204 Imicluzolc ..................................... 2.56 1,2,4-Triwolc .................................. !260 I

- -_.-

-

Tnble I summarizes tlie boiling points of a nmnbcr of five-membered licterocyclic compounds and illustrates the unusually high boiling points

G

Chemistry of Classes and Derivatives

of iiuidazole and 1,2,4-triazolc. Pyrscole also boils rather high in coio-

parison with furan, and yyrrole, dthougli it does not differ. significantly froin them in inolecular weight. Tile boiling point of iniidazole is strikingly lowered by the introduction of 8 methyl group into the 1-position, but is not significantly affected by the introduction of a inctliyl group into the 4(or Ti)-position. Even tlic introduction of an amyl group, which doubles the niolecular weight, results in a substance boiling lower than the parent ring system. Tliesc results demonstrate that the free iinino hydrogen is, to a certain degrec, responsible for the observed high boiling points of imidazoles (Table 11).

.

TARLE 11. Effert of Snbstitiients on the Boiling Point of Imidawlc Compound

B.IL,'C. (?!XI mni.)

Imidazole ...................................... 258 198 I-Methyl- ..................................... 4(or !j)-Methyl- ............................... 264 1-Propyl- ..................................... 223 1-Amyl- ....................................... 245 1$-Dimethyl- ................................. 205 1-Ethyl-%methy I- ............................. 211 1-Methylb-clilowi- ............................ 202 1-Methyl-4-chlqro- ............................ 245 200 1,4-Dimethyl- ................................. 1,SDimethyl- ................................ 220 1-Phenyl- ...................................... 277 2-Phenyl- ...................................... 340

Table 111 suniinarizes the melting points of a nuinber of imiclazolcs. ITcrc again it will be noted that the introduction of substitucnts into 1 . 1 ~ I -]wition of the imidazole ring hns a striking lowering effect. TAl3T.E 111. IIclting Points of a Number of Tmidnmles ('mtq~ountl

Imidazola ....................................... I-Methyl- ...................................... 2-Methyl- ....................................... 4(or Fi)-MeiItyl- ................................. 1-Phenyl- ....................................... 2-Phenyl- ....................................... 4(or I)-Ptic~nyl- ................................. ....................................... I-Ben& 2-Benzyl- ........................................ 4(or S)-Bengyl- ................................ 4.5-DiphenyL. ................................ 2-Methyl-4,5dipheuyl- ......................... l-Methyl-4,6-diphenyl- ..........................

!bf.p..

oc. 90

-6 140-141 55-56 13

148-149 133-134 71-72

125-126

82-84 228 240

158

3. s%luhility

Tlic sulultility o l iiiricl:txolc is high ia poltrr :rncl low in I I O I I - ~ I O ~ ~ U solvents. At rooiii temperature it is so cxtremely soluble in water that quantitative data on its solubility have not been obtained. The base is somewhat soluble in benzene ; however, at room temperature its solubility in this solvent is rather limited. Cyclohexane is a poor solvent. 4(or 5 ) Methylimidazole exhibits good solubility in benzene. The N-substituted imidazoles are in general much more soluble in non-polar solvents than are the imidazoles with a free imino hydrogen. Quantitative figures on the solubilities of imidazole in benzene and in dioxsne, and of 4(0r 5)-methylimidazole in benzene, are given in Tables I V and V. TABLE IV.Solubility of Imirlszole in Bcnxcne and in Dioxane (3) 1.1

Temp., "C.

ihxt-ne

----

_.--_--

eM.7 4 1.o 42.2 42.8 448 45.7 478 40.0 51.2 .i1.8 52.9 56.2

_t

Molnli~y

0.198 0.268

0.486

0.888 1.196 1.524 2.38 3.00 4.03 5.38 6.77 9.23

Ihxnnr

'renrp., T.

14.7 17.9 21.9 23.0 32.7 38.0 39.4 46.8 55.8

Molslity

3.62 429 4 9.3 6.17 7 48

9.46 10.5 143 19.3

TAHIJ! V. Solnbility of 4(0r 5)JiethyIimitlnzole in Renzene (3) Temperature. T.

I _

---

32 16.8 21.1 25.4 3.3 31.4

Molnlitp

4.57 6.0i

687 7.44 8.24 8.54

4. Molecular Weight and Degree of Association

._ -. -

The determination of the molecular weight of iiiiidazolc and of 4(or 5)methylimidazole by the vapor-density method indicates that tliese compounds are not associated in the gaseous state (4,5). The theoretically expected molecular weight of 68.0 is found for irnidazole by the use of Vietor Jfeyer's vapor-density method at a temperatiire of 306" (3). However, when thc inoleculnr weights of these compounds are determined

Chemistry of Clnsaca nncl Dcrivs t.ivrs

8

11ythe cryoscopic'or cl)ullioinetqi.ir~ iii&wis in non-polar snlveiif s, striking deviationP from ideal behavior isre abserved. Most unusual in t,hk respect is the cryoscopic behavior of 4 (or 5 ) -mctliylimidazole in hpnsenc: solution. A t I\ conccntmtion of 0.6 7n (nz = molalikyy)this stihRtance ex-

I

1

I

I

I

I

I

I

1 2 3 4 5 6 7 CONCENTRATION. 9. mols. x IO'*/IOO g. of solution

I

8

Pig. 1. Associution-concentration curves of a number of iniidnaoles in napht.halcne (6): t 1) imidazolc; (2) 2,4~trimetliylin~idozole ; (3) benzimidiizole; (4) I-c.r~il~etho?rybenzirnidaeoIe;(5) 1-niethgl-4.5diphen~limidnxolc. y p r e n t molecular weight Association factor. a = formula weight

hibits an sppsrcnt molecular weight of 1500. Tliis represents almost twenty times thc cxpected formula weight of 82. At liiglier concentrations R slight rise in the apparent molecular weight is notcd, which reaches a maximum a t a concentration of 1 n z and slowly decreases a t still higher concentratsions. Similar behavior is observed with imidazolc, which exhibits~a normal molecular weight only in highly dilute solution.

I. General Properties and Structure of Imidazoles

9

The cryoscopic behavior in naphthalene of a great number of imidasoles and benzimidazoles parallels that observed with imidazole and 4 (or 5 )-methylimidazole. Of importance is the fact that substitution of the imino hydrogen by alkyl, aryl, acyl, or carbethoxy groups invariably leads to compounds exhibiting little association (6). A set of typical association-concentration curves for a number of imidaeoles obtained by the cryoscopic method in naphthalene is illustrated in Figure 1. Ebulliometric molecular weight determinations in boiling benzene also yield abnormal results. For example, 4 (or 5 )-metliylimidazole a t a concentration of 0.4 m exhibits an apparent molecular weight of 190, which is approximately twice the formula weight. Imidazole is also appreciably associated in boiling benzene, since at a concentration of 0.4 m a molecular weight of 250 is observed (approximately four times the formula weight). It is of interest to note that imidazole in aqueous solution exhibits a normal molecular weight which changes little with increasing concentration. TABLE VI. Viscosity of I3enzenc Solutions of 1micl:izolr and 4(or 5)-MetliyIimidazole (3) Compound (tonap., "C.)

vvlcOs1ty

0.073

0.W8 0.0649

.................................. 0.036

Iinidazole (30")..

Imidnzolc ( 5 0 " )....................................

0.146 0.146 0.416 0.483

........ 0.040

4tor 5)-Methylimidazole (30")......... ... ..

4(or 5i)-Methylimidazole(50').

Specif0

Molality

0.080

0.242 0249 0.476 0.493 0.607 1.075 1362 2.w 2.848 3.738

..................... 0.242

0.249 0.475 0.493

0.801

0.0106

0.0410 0.1500 0.1686 0.0071

0.0354 0.1 187 0.127; 02926

0.3262 0.4113 0.7801 0.9911 1.6524 2.3138 3.1560 0.0910 0.0030 02140 02370 0.3079

All these findings point to a high degree of trstiociation of the itiiidazoles in non-polar solvents; that the association is dependent on the presence of a free imino hydrogen is evidenced by the low degree of association of tlie N-substituted imidazoles and benzimidasoles. 5. Vlecosity

Tlie specific viscosities of benzene solutions of iniidszole and 4(or 5 ) ~uetlryliiiiidazoleare given in Table VI (p. 9). Solutions of pyrrole or of pyrazole in benzene have approximately the same viscosity as tlic pure solvent, and negligible variation of the specific viscosity with increasing concentration is observed. This suggests little association. Tlie specific viscosity of solutions of iiiiidazolc and 4(or 5 ) -methylimid~bsolc,011 t Iic other band, increases with incrciising concentration (see Table IT),n bcliuvior pointing to tlie pwacnce of long-chin aggregates. 6. Dipole Moments

Most valuable infornintion on the fine structure of organic niolcculcs iiiay be gained from an exact knowledge of tltcir dielectric properties, sincc tlic magnitude of tlic dipolc iuotiiciits is iaciicntivc of the cliarge distribution within their structures. Unforttinatcly tlie esperjmental 11i:iterial 011 iinidazolcs is rather limited, clipole moments being avni1al)Ie only for imidazole, 4 (or 6) -iiietliyliinidnzole, l-riietliyliii~i~l:rgolc,uticl h i i ziinidazole. Tlie results are sumninrized in Table VII.

Again tlie high degree of ussocitation of the imidazolcs containing R free iiriino group in non-polar solvents reflccts itself in the dipolc?moments. Thus the mornent of I -methylimidazolc witen iiieasured in bctizenc solution is little dependent on the concentnrtion, in contrast to that, of iiiriclazolc ~vl~icli v:iric?s t,o R consiclcr:rldc extent as illiistr:\ted in T:hIc VTTT.

I. General l’rolwrtics

a i d Strtvt.urc of Iniitlnzolcs

11

TABLE VITI. Variation (with Conccntration) of thc Dipolc IIonimit of Imitlnxole in Benwne (7) Mole fmtion of cnlute

--

Dipole moment. Debye unib

o.oo5051 0.001140 O.OOO233

5.02 4.42

3.93 7. Spectroscopic Properties

(a) Ultraviolet Absorption Spectra

The siiiiple iinidazoles fail to exhibit selective absorption in the ultmviolet region t8,9,. Sclcctivc absorption is observed in iniidazolcs in wliicli thc iniidltzole ring is conjugated with a carbonyl group, such as in the imidazolecarhoxaldehydes and irnidazolecarboxylic acids. Also, certain functional derivatives such as the imidazoletliiones exhibit characteristic absorption maxima in the ultraviolet region. The spectra of these coiiipounds will be found in the appropriate sections.

( b ) Ranian Spectra The Raman spectra of various iiiiidazoles have been investigated, and thc reader is referred to the original literature on this subject (10).

( c ) Chemiluminescence A nunibcr of arylimidaroles exhibit chemiluminescence when exposed the action of an oxidizing reagent in alkaline milieu. This interesting phenomenon was first observcd by Radzisrewski (11) who found that a solution of 2,4,5-triphenylimidazoIc (lophine) in potassium hydroxide emitted light when it was shaken with air. He was struck by the intense light production and described his observation as follows: “The phenomenon becomes rather spectacular on a large scale; I employed 100 g. of lophine and 300 g. of potassium hydroxide in alcohol for my experiments. The devclopmcnt of light was so intense that it was possible to see the faces of the observers at a distmce of two to three feet, and at a distance of two and one half to fivc ccntinieters the numbers and hands of a pocket watch could be recognized.” The addition of an oxidizing agent to n solution of lopliine in alkali brings about a marked increase of the cheniilumincscence. Optimal effects are obt-ainedwhen a solution of lopliine in ethanol, methanol, acetone, or ’ dioxane is treated with an oxidizing reagent such as hypohalite, pota,.~slllni to

Y

13

TABLE IX.Density, Refractive Index, and Molar Refractivity of Iniidazole und Derivatives at Various Temperature* (3,171 Imidazole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . , . . .

4(or +Methyl-.

.. . . . . . . . . . . . .

Temperature

Density. dd

95.0 100.9 110.0 153.0 205.0 14.3 18.0

1.0360

(0, OC.

Compound

.

. , .... . . . .

.,.

50.0

60.0

1-Methyl- . . . . . . . . . . : . . . . . . . . . . . . . . . . . . . . . . . . . . ................................ I-ISoamyl-. .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . l,%Dimethyl-. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1-Ethyl-%methyl- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1-Methylb-chloro- .. .. . . . , . . . . . . . . . . . . . . , . , . . . . I-Methyl-4-chloro-.. . . . . . . . . . . . . . . . . . . . . . . . . . . l-Ethyl-%methyl-5-chlo~~. .. . . . . . . . . . . . . . .. . . . l-Ethyl-%mthybhbr+. . . . . . . . . I-Phenyl- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I

70.0 110.0 153.0 20.5 19.6 19.7 16.1 21.8

20.5 17.7 19.8 19.8 16.8 15.4

-

1.om 0.9920 0.9370 1.M16 1.0360 1.0160 1 .m 1 0.9691

.oom

0.9380

1.0325 0.9i05 0.9427

''C

1.48075 1,47625

-

1,50367 1.50115 1.a922 1 ,48627 1.-18227 I

1.2500

1.4885B 1,47671 1.47114 1.48665 1.4a301 1.50630

1.1415 1.1598 1.139i

1. m o 1.49519 1.a364 1.59335

1.m 0.9807 1.2561 1 .a83

1 SO783

"He

(UjP

1.48428 1.48006

-

fiF

1.49442

1.48W

-

I

1 ,50774 1.50572 1.4BfI8 1.48!494 1.48553

1.51750 1.51499 1.50284 1.49982 1.4953S

-

I

1.43244 1.48021 1.47425 1.49024 1.48660

1 ,51009 1.51181 1.51308 1.49888 1.50223 1.59999

1.50157 1 .WQ

1.4m5 1.49926 1.49516 1.51958 1.52121 1,52259 1.50731 1.51088 1.61650

.w,

ferricyanide, hydrogen peroxide, or hemoglobin (12-15). 9 variety of substituted aryliinidazoles such as 2,4,5-trb (p-methylphenyl) - , 2,4,5tris (p-methoxyphenyl)-, and 2,4,5- tris (p-chlorophenyl)-hidasole, or substances like 4,5-diphenyI-2-methyl-, 4,5-diphenyl-2-ethyl-, 4,5-diphenyl-2-isopropyl-, and 4,5-diphenyl-2- (p-methoxyphenyI) -imidazole cxhibit clieniiluiiiinescence under the above-mentioned conditions ( 16). Ainarine (2,4,5-tiiphenyl-2-iinidasoline)behaves similarly (14). Imidnzole exhibits a weak degree of chemiluminescence upon exposure to hydrogen peroxide (12). The emitted light exhibits a continuous specti-um ranging from 48006OOO A, with a maximum at 5300 A. 8. Miscellaneous Physical Properties

Information on refractive indexes, densities, molar refractivities, surface tensions, heats of fusion, and heats of solution of imidaaole and 4(or 5)-methylimidazole is suinmarized in Tables IX, X, and XI. TABLE X. Surface Tension of Imidazola and 4(or 5)-Methylimidarole (3) Comwuad

Imidazole

..........................

4(ori)-Methyl-

....................

Temperature, "C.

Surface trmsion, dynidcni.

110.0 150.0 205.0 20.0 66.0 110.0 153.0

36.82

33.85

30.05 38.70 3621 32.36 29.28

TABLE XI. Heat of Fusion 2nd Heat of Solut.ion in Benzene at Varying Concentrations of 4 (or 5 )-3Iethylimidazole (3) molity

Heat of solution. eal./mole (21')

0.13 0.22

-3210 -2170

-

Heat of fusion, cal./mole

-2840

-

C. Chemical Properties 1. Basic Strength

Iinidazole is a monoacidic base having the ability to form crystalline salts with acids. The melting points of a nuiiiber of characteristic imidazoliwn salts are listed in Table XII. The basic nature of the imidazoles is due to the ability of the pyridine nitrogen t o accept a proton. Substituents influence the basic strength of imidazole in the inanner illustrated in Table XIII. The introduction of methyl groups into the

'I'.iHLE S I I . Alr4ting Points of %It

.

B

Xiimbt-r of Imidnnole Salts Mp., OC.

Xitrate ................... 118 Chloroaurate ............. tlec. 100 Chloroplatinate ........... clec. 200 Dimolybdatc ............. Picrate .................. 208-212 Flavianate ............... 224-220 Dilituratc ................ Acid oxaliitr .............. 232,252,225 Acid tartrutc .............. 202 Benzoate ................. w

..

. . . _ I

iniirlazole ring increases its basic strength. This is explicable in terins of the electron-releasing properties of the inctliyl group, which tends to increase the electron density about the pyridinc nitrogen. The situation parallels that observed in the pyridine series, where the basic strength of a-picoline is also higher than that of the parent ring system (33). This increase in basic strength has been attributed to a combined inductive and resonance effect (hyperconjugation). Siinilur considerations may apply to 2-methyliinidarole, where hyperconjugated states of the type depicted below are indicated. The introduction of a methyl group into tlie 4( or 5 )position of the iniidazole ring also increases tlic basic strength, but tlic

effect is lcss pronounced than that of the 2-nietliyl group. Syiiiiiictry considerations iiiiglit ofler mi cxplanation for this different-c. Tile 2-mcthyliinidazolium ion represents a highly symmetrical structure with two equivalent contributions, in contrast to the 4(or 5 )-metliyliinidcizolium ion methyl with two non-equivalent contributions. The introduction of group into both the 2- and the 4(or 5)-position causes u further incrcasc in basic strength. Electron-attracting groups such as tlie plieiiyl group, the nitro group, or a halogen, decrease the basic strength. A few qualitativc observations on tlic basic strength of N-nlkylnitroimidsroles are of interest. A coiiipsrison of 1-methyl-5-nitroiinidazole and 1,2-dimethyl-5-nitroimidazole with their respective 4-nitro derivativcs indicates that tlie 5-nitro compounds are the stronger bases (34%). It

I. General Properties and Structure of Imidaaoles TABLE XIII. Basic Strength of a Number of Imidazoles (30,32,32a) Compound

Imidazole 1-Methyl%Methyl4(or WMethyl2,4(or 2,5)-Dimethyl2,4,5-Trimethyl2-Phenyl4(or ti)-Phenyl4(or S)-Hydroxyrnethyl4(or S)-Carboxy4(or S)-Carbethoxy4(or S)-BromoHistamine

PKa

6.95; 6.W 7.26 7.88 7.52 8.36 8.88. 6.39

15

--

6.00

6.38 8.08'

3.06'

3.80. 5.98'

Measurementa in 233 per cent aqueous ethanol at 30'.

seems logical that the structure' in which the nitro group is located in close proximity to the electron-donor system (pyridine nitrogen) should represent the weaker base. CH L

CHa I

I

H-C' N'f-CHI

O&-F'N'f-CH,

H-C-N 1,2-Dimethyl-5-nitroimidazole (stronger base)

II OnN-C-N

1,2-Dimethyl-4-nitroimidazole (weaker base)

2. Pseudoacidic Character

In addition to its basic nature, imidazole also exhibits weakly acidic (pseudoacidie) properties. It forms aalts with metals of the general structure shown below. Most important among the salts is the sparingly solu-

ble silver salt, which is precipitated when imidazole is brought into contact with ammoniacal silver solutions. In the presence of ammonia, insoluble salts with cobalt and einc are also obtained (36,37). The reaction of imidazole with a Grignard reagent results in the formation of an imidasole magnesium halide (38,39).

Chemistry of Classes and Derivatives

16

H

The pseudoacidic nature of iiiiidttzole depends upon tlie preseiice of an unsul),staitutediinino group, and iniidazoles having this structural requirement forni sparingly soluble silver stilts in the presence of aminoniiical silver solutions. Many imitfazoles foriu insoluhlc salts witli cuprous ion in the prcsence of animonia (40). Iinidazole dissolves in liquid aiiinioni:i, forming H clear solution from wliich it is regencrated on cvaporntion of tlir aolvcnt. The addition of iiictals or of nietal :iniidcs to sueli a solutioii i*csulteiii riilt forination. Tfie sodiuiii, potnssiuiii, cdc:iu~ii, niid magnesiuiri sitlts ttrc obtained in this iiiann~r. Tlicsc stilts ;ire unstahlc in the prcsc.iic.c of wiLtw, :rnd hydrolyze with tlic ioriiiation of iiiiidnzolc iriid inctullic. Iiyli.oxitlcs (41 ) . A coinpariaon of the c*oiiiluctaiiccof liquid miinoiri:i sohitions of iiiiirliizole and of pyrrole deiiionstrates the former coiii~~oriiitl to rcprcscnt the stronger acid. Elcrtroiicg~ttivcsubstituents increase tlic nridic. propertics of tlic iiiiidazolcs by tlcc*rcxsiiigthe electron density itl)out tlic ~~yrrolc nitrogen. J.ol)liiiic is ;L st rongcr acid tliuii iiiiit1:izoIt~. I A c iliridiwdc, lopliiiic foriiis salts ul)oii tinatiiicnt with metals or iiictal :tiiiidcs in liquid iiiiiiiionia solution (41). 2,4,5-Tril~roiiioiii~idaz~le is a strong enough avid to dissolve in tiqueous sodium c:irl)onate solution (42). 3. Chemical~Stabilityand Aromatic Character

Altliougli a detailed discubsion of tlic clicniical behavior of tlic iiiiiclazoles will represent the subject of Iiltcr cliaptcrs, it seems pertinent to suiii . tiiarizc briefly a numlm of their kcy propertics prior to consideration of structure. Outstanding is tlic pronounced cliciiiicitl stiil)ility of tlic iinidazolcs. 'I'licy are rcsistant to tlic most drastic trcatntcnts with :scitls anti 1)asca. Kxposure of iinidazolus to the action of 11ydrogc.uiotlidc i r k teiiiiwrzttr1rcs up to 300" Iias little effect, and the iniidnzolc- ring 1-csistsclttulytiv hydrogenation to it reinarkablc degree. A number of I)enziiiiidazoles, such us !&inethyl-, 2-ctliyl-, and 1,2-dimcthyl-bensin~id~zole, in tlie presence ol' Adains cstulyst and glacial acctir acid undergo hydrogenation iii tlw !)cnzcnc portion with the foi-nintionof the rorresponding tetrahydro derivntiws. The iinirlirzolc portion roirirriiis unuffcctcd (43-45).

I. General Proprtics and St.nicturc of Imidnzolcs

H H

17

I

€I--& +N H’ ‘C’

H H’ Lophine undergoes catalytic hydrogenation over Willstiitter platinum catalyst in glacial acetic acid?and is converted into 2,4,5-tricyclohexyl-2imidazoline (46). Imidazole is stable toward chromium trioxidc (a), but is readily attacked by pot.assium permaneanate and hydrogen peroxide with the formation of oxamide (47,481). Benzoyl peroxide in cliloroform solution also attacks imidazole readily with the formation of urea and aninionia (49). The imidazoles undergo typical “aromatic” substitution. They can be halogenated (see Chapter IV),nitrated (see Chapter V, Section A-1), sulfonated (see Chapter VI, Section B ) , and hydroxymethylated (see Chapter 111, Section B-1-(a)), and exhibit the abi1it.y to couple with diazotized aromatic amines to form azo dyes (see Chapter V, Section B-1). Despite t.he presence of an “imino” group they fail to react with nitrous acid.

D. Structural Considerations

1. The Classical Imidazole Formula

As has been stated previously, the discovery of irnidazole dates back to the year 18.58 when Debus (1) obtained the compound for tlic first time. He recognized the basic nature of the substance and esta1)lishetl the correct empirical composition as C3H4Nl,but did not propose a structural formula. Although this represented the first description of the parent ring system, imidazole derivatives had been known prior t o 1858. For example, 2,4,5-triphenylimidazole (lophine) was initially synthesized by Laurent (50) in 1845. Recognition of the close chemical relation between lophine and imidazole was of a later date. The first chemical study of iniidazolc was carried out by Wyss (42), wlio substantiated the work of Debus and established a number of fundamental points about its general behavior. He recognized the amphoteric nature of the coinpound, and although lie was able to alkylate the base, he failed to achieve its acylation. The great stability of imidazole toward hydrogen iodide, and the formation of a tribromo derivative, also were reported by this investigator. Based on these findings, MTyss proposed the structural formula: 0

Chemistry of Classes and Derivatives

18

Imidamle (Wyss, 1877)

Most fruitful for the further dcvclopinent of the constitutional problem was the suggestion by Radzisxcwski (51) that lophine may be an imidazole derivative. Considerable progress on the constitution of this latter compound had already been made a t that time. Based on t-hc partial structure advanced by Fischcr and Trosclike (52), Japp and Robinson (53)in 1882 proposed the currently accepted, classical structmc of lophine. Almost simultaneously Radziszewski (51) prepared lophine

Fischer, 1880

Japp, 1882

Proposed structures for lophine

Radeiszewski, 1882

by the interaction of benzil and benzaldehyde with ammonia and, based on this synthesis, proposed a structure for lophine which differed from the Japp formulation in the distribntion of the double bonds. He also postulated for imidazole a formula not containing an imino function, since in his opinion only such a structure was capable of explaining the failure of imidazole to undergo acylation and its inertness towards nitrous acid. These views were not shared by Japp who put forth an imidazole formula

Radziszeaski, 1882

H

Japp, 1882 Proposed structures for imidamlc

with an arrangement of the double bonds analogous to that proposed for lophine (54). Japp accepted Radziszewski’s suggestion that imidazole representa the parent ring system of Iophine but pointed out that his formula was better suited to explaining the chemical behavior of the com-

I. General Properties and Structure of Imidazoles

19

pound. He reasoned, for example, that. the structure proposed by Radziszewski would be expected to form a tetrabromo derivative, whereas imidazole had been shown by Wyss to be brominated with the formation of a tribromoimidazole. Also, he felt that his structure was better suited to explaining the great stability of imidasole toward hydrogen iodide. Although the Japp formulation was later shown to represent the correct classical structure of imidazole, neither Japp nor Radsiszewski presented conclusive evidence for the correctness of their postulated formulas. It remained for Bamberger (55) to furnish the most convincing piece of evidence for the structure of imidazole when he oxidized benzimidazole to 4,5-imidazoledicarboxylicacid and by decarboxylation of this compound obtained imidazole.

dxH

H

H

H I

oxidation-

HOOC 2. Current View8

Any theory concerning the structure of the imidazoles must offer plausible explanations for the following characteristic features of this class of compound: (1) Their pronounced “aromatic” properties, as reflected in great cliemical stability, saturated character, and typically aromatic substit ution behavior. (2) The pseudoacidic nature of the imino hydrogen. (3) The high degree of association in non-polar solvents and the idge dipole moments. (4) Many other properties as discussed in succeeding chapters. The classical formula of Jspp fails to satisfy these criteria and thus is not a suitable representation of the imidazole molecule. The azoles are, without exception, substances exhibiting a typical “aromatic” behavior. Their much more pronounced polar character differentiates them markedly from benzene and from other five-membered lieterocyclic compounds, such as furan, pyrrole, and thiophene. This polarity reflects itself in unusually high boiling and melting points, increased water solubility, and high dipole moments. Despite these differences in fundamental behavior, explanations similar to thoae,currently in use for characterizing the state of the benzene molect~leitlay he profitahly applied t.0 these heterocyclic systems. The

20

Chemistry of Classes and Derivatives

properties of benzene are linked to a characteristic six-electron resonance system. The azoles and many other lieterocyclic ring systems contain similar electronic configurations, as illiist,rnted below : €1

H

H I

N

H

T"yH

H

Pyrrole

N

Tliiazole

111 coiitxast to tlic situation in lm~zciie,wlicre circli imd,liiiic groiii) ooiit*ributesone T electron, tlie different ring partners in tlie Iic!terocyclic: coiiipounds do not make equal contributions to tlie resonance systeui. Thc i i i c t h e groups and the tertiary nitrogen contribute one electron each, in contrast to tlie imino group and atoms sucli as oxygen or sulfur, which are the source of two electrons. Pertinent in connection with the present discussion is ti consideration of the pyrroles and the pyridines. Pyrrole is best represented as a resonuiice hybrid to which tlic classical structure A and two pairs of syminctrical structures B and C m:dx significant contributions (56). This foriiiui:it.ion, which receives support. flwn hond-distancc n i e a ~ ~ i r ~ i ~ i (57 c n t)s :uid clipolc nioiiicnt t b t . a (hb) , offers a pkiusiblc explanation for tlic!

H H

t ,

H A

H

€1

I

B

H

H C

chemical behavior of pyrrolc. Its acidic character, for example, may be tlic result of the illustrated T electron distribution which places a positive vhargc o i i tlic iiniiio nitrogen, tlius facilitating the release of a proton. Pyiwlitliiw, tlic r:hirtrtetl ittrdogt1c of pyrrok, wliic.11 lacks this resonnncc system, I)eliiiws likr :L typi(.:il sc9c~oiitl:wyiainiiic.

a

The acidic nature of the imidazolcs is explicable in a similar manner, and the imino nitrogen will be referred to as the pyrrole nitrogen. Characteristic for the aaoles is the presence in their molecules of a tertiary nitrogen which endows them with basic properties. The properties of this nitrogen are strikingly similar to those of the nitrogen in pyridinc. Accordingly, this function will be designated AS the pyridinc nitrogen. The presence of an electronegative nitrogen in pyridine is responsible for the characteristic behavior of its ring system. Sincc it seems reasonable to assume that the tertiary nitrogen in the azoles will exert a similar influence, a brief consideration of fundamental pyridine chemistry is in order. Using its affinity for electrophilic reagents as the criterion, pyridine is less reactive than benzene. Pyridine fails to undergo the Friedel-Crafts yeaction, and extremely drastic conditions are required to bring about its sulfonation, nitration, or halogenation. Another characteristic property of pyridine is its ability to undergo nucleophilic substitution, as exemplified by its transformation into 2-aminopyridine by treatment with alkali amides. I n contrast t o electrophilic reagents which attack the pyridine ring in the 3- and 5-positions, substitution by nucleophilic reagents occurs predominantly in the 2-, 6-, and (to a lesser degree) in the 4-position. These experimental findings indicate a higher electron density in the 3and 5-positions as compared to the 2-, 6-, and 4-positions, and a general deactivation toward electrophilic substitution. Pyridine may be represented by a' resonance hybrid with contributions from two KekulB-type structures A and B and from structures C, D, and E. These latter contributions picture the electron drift toward the nitrogen atom, which is responsible for the low reactivity toward electrophilic substitution.

A

B

C

D

E

The presence in the imidazole structure of an acidic pyrrole nitrogen and a basic pyridine nitrogen explains the amphoteric nature of these compounds. Qualitatively, the imidazoles may be regarded as a "cross" between a pyridine and a pyrrole. Thus one could expect a deactivating influence toward electrophilic reagents caused by the pyridine nitrogen, which to a certain degree is offset by the electron-releasing properties of

n

Chemistry of Clrrsses and Derivatives

the pyrrole nitrogen. The chemical behavior of the imidazoles is in agreement with this admittedly crude picture. A comparison of the dipole moments of a number of azoles, as recorded in Table XIV,shows that tetrazole, 1,2,4-triseole, and imidazole exhibit the largest moments of the group. It is of interest to note that

TABLE XIV. Dipole Moments a.nd Dissociation Constants of a Number of Azalea (7)

D Pyrazole ................. 157 Thiazole ................. 1.84 1,2,3-Triazole ............. 1.77 1,2,4-Triaz.ole ............. 3.17 Imidazole ................ 3.84 Tetmole ................ 6.11

PKa

Compound

2.53 2.53

.-

----

-

2%

8.95

-

--

these ring systems embody a common structural element, namely two nitrogens separated by a methine group. This particular arrangement inust, in part, be responsible for their highly polar character. Azoles which do not contain this particular arrangement, such as 1,2,3-triazole and pyrazole, have considerably smaller moments. Contributions from n typical amidine-type of resonance system to the state of the imidazoles, t,hc 1,2,4-triazolesl and the tetrasoles, are thus indicated. These contributions done, however, are not capable of explaining the acidic nature of the

H-C\ /

B

N-

..

N-

@

c--c

//

H I

N-

"-%.N. 8

imidazoles, as will be apparent froin a coinlxtrison of the properties of the imidazoles with those of :he 2-imidazolincs. Thesc lnttcr cornponiuls. also possessing an amidine-type resonance system, are n e i t h r ninpitot(8ric. nor do they exhibit the pronounced association whirl1 is so typical of t l w imidazoles (6).

*

I. General Properties and Structure of Imidamles

23

From an inspection of Table XIV it will be apparent that there is little correlation between the relative magnitudes of the dipole moments and the basic dissociation constants in the mole series. For example, the moments of 1,2,4-triazole and of imidazole are of the same order of magnitude, but their dissociation constants are markedly different. This observation is in disagreement with the postulated amidine resonance which predicts an especially high negative charge on the pyridine nitrogen in azoles exhibiting a high dipole moment. Although it is impossible with the experiinentrzl material on hand to offer a definite explanation for the high basicity of the imidazoles, there seems to be little doubt that the amidine-type resonance and the highly symmetrical nature of the imidseoliuin ion must be important contributine factors. Two non-equivalent structures A and B contribute to the state of the uncharged molecule. These would be expected to differ in their energy content.

B A

B

The addition of a proton to the pyridine nitrogen leads to the formabion of the positively charged imidazolium ion .~.hich receives contributions from two exactly equivalent structures. The higher stabilization (“addi-

lional ionic resonance effect”) of the imiduzoliuin ion as compared to the uncharged molecule might be expected to increase the basio strength. A final decision regarding evaluation of the structure of the imidazoles must await the establishment of the bond distances and bond angles, In analogy to other, more thoroughly investigated, heterocyclic ring systems, imidazole may be represented a8 a resonance hybrid with contributions from structures shown on p. 24. A set of similar contributions in which the functions of the nitrogens are reversed may account for the other tautomer (59). This formulation could account for the acidity, the

Chemistry of Classes and Derivatives

24

aromatic character, the substitution I)eliavior, and the high dipole 1110111ent of imidazole. The classical formula will be employed throughout this book as a representation of t,lie imidazole molccule. The relation between degrcc of resonance and clieinicrrl stability iii the imidazole series is well illustratcd by a comparison of the stability toward hydrolysis of tlie imidazoles with that of tlie 2-imidazolines and the imidazolidines. The highly stabilized iiniclazole ring withstands Iieating at 180’ with concentrated hydrogen ohloridc. The 2-iinidazolino ring. which still retains the nniidine-type resoiiance systein, hydrolyzes wit1I the formation of a monoucylated etliylenediainine on short refluxing witli dilute mineral acid. The imidazolidine ring unstabilizcd I)y resonance is highly labile, and on short exposure to coId dilutc mineral :wids, is Iwokeii with the formation of an aldehyde and ethylenediumine.

H

€I

I

H H

Imidazole

-

2-linidazolinc Decreasing stability

ir--

x

Iiiiidazolidiric

Inquiry into tlic physical Iwopertim of tlic iiiiic1:teolcs Iius rcvcalct I n high degree of association for tlicsc coniyouncls i i i ~ion-polar solvents. Tliis property, wliicli depends on the presence of ;I free iiiiino hydrogen, is explicable in tcrins of hydrogen bonding between the pyridinc. nitrogen of one inoleculc and t.he iniino hydrogen of another. The rcsulting hydrogen-bonded ~nncroinolcculcsmay be visualized in t l i c b n i i w

I. General Proprrties and Structure of Imidamles

25

ner shown below (6). Such a formulation offers a plausible explanation €or the non-association of the imidazoles in polar solvents. The size and

1

x l -

.**N’N-H*.N’

H H

H

H

x x w x i I - i H H H

N-H.*N

X-H**N

N-H..N

N-H..N

H

H

H

H

H

1

I

H

H H H - . H - - N ~ N . . M - ~ ~ ~ . . E Z - \NN . . I I - A N . . E I - - N

H

N-H...

H

H

R

H N..H-NAN...

I H- tH tH -H iH HH H H H K H H H H

H

shape of the aggregates are unknown; however, the observed increase of the specific viscosity with concentration of benzene solutions of imidazole indicates the presence of long-chain polymers. Certain imidrtzoles such as 2-to-hydroxyphenyl) -4,5-diphenylimidezole, 2-(o-liydroxyphenyl j benzimidazole, or 2- (o-aminophenyl) benzimidazole exhibit little association in noa-polar solvents, despite the presence of a free imino group. This observation is explicable in terms of intramolecular hydrogen bonding. The formation, through hydrogen bonding, of a quasi-six-membered ring between the ortho substituent and one of the imidazole nitrogens, as illustrated for 2-(0-hydroxyphenyl) benzi-

midazole, may successfully compete with the formation of the abovementioned association complexes. The coplanar structure for 2- (ohydroxyphenyl) benzimidazole receives support from spectroscopic evidence (60). The introduction of a hydroxyl group into the meta or para positions of 2-phenylbenzimidszole causes little change in the ultraviolet absorption spectrum. The spectrum of 2- (o-hydroxyphenyl) benaimidazole, on the other hand, is markedly different,

26

Chemistry of Classes and Derivatives

E. Tautomeric Character

Imidazoles containing a free imino hydrogen and a substituent in the 4- or 5-position, or two dissimilar substituenta in these positions, might be expected to occur in the isomeric forms illustrated below. These isomeis differ in the position of the imino hydrogen which may be

H

H

attached to either of the two nitrogen atoms. The removal of this hydrogen or the addition of a proton to the pyridine nitrogen leads to the formation of ions in which the possibility for isomerism has been lost. Both forms are thus transformed into identical salts.

Many attempts to prepare such pairs of isomeric imidazoles have resulted in failure, and only one compound is obtained where the synthetic routes employed might have led to the formation of isomers. For example, 2-amino-3-pentanone and 3-amino-2-pentanone afford the same 4(or 5 )methyl-5 (or 4) -ethylimidazole when they are subjected to the WohlMarckwald imidaeole synthesis (61,62). (See Chapter 11, Section A-5.) The separate existence of t-woisomeric forms of a given imidazole contain-

-

l:fr H I

I. General Properties and Structure of ImidszoIes

27

ing an imino hydrogen has been claimed from time to time. Most of these cases were later interpreted in terms of polymorphism rather than tautomerism. A classical example is the compound 2,4(or, 2,5)-diphenylimidazole. This substance exists in two forms melting at 168' and 1 9 3 O , respectively. The lower melbing modification results from the condensation of a-aminobenzyl cyanide with bemaldehyde and also from the treatment of 2,6diphenyloxazole with ammonia (63),while the higher melting form is obtained from the reaction of benzamidine with m-bromoacetophenone or by the interaction of a-hydroxyacetophenone with benzaldehyde in the presence of ammoniacal cupric acetate (40,64). Both modifications afford identical salts from which either form of the base can

1 L

be regenerated. Short boiling of the higher melting base with ethanol

leads to the formation of the lower melting compound (65). This experimental evidence indicates polymorphism rather than isomerism (6). The finding that only one isomer is obtained by synthetic procedures which should have resulted in the formation of two is explicable in terms of tautomerism. It doea not, however, establish the tautomeric character of the imidasoles, as a difference in stability of the two isomers might also favor the formation of only one compound. The virtually tautomeric character of 4 (or 5 )-methylimidaaole follows from its behavior on methylation, leading to the formation of a mixture, separable by distillation, of 1,&dimethyl- and 1,4dimethylimidazole (66,67). Thus the compound reacts as if it were a mixture of 4-methyl- and 5-methylimidseole.

28

Chemistry of Classes and Derivatives

CH, 1,5-Dimethylimidnzolo

1 ,.l-DimcthylimidnzoIc

Iiiiidazoles containing a, free iiiiino lrytlrogcn arc thus virtually bausystem and react like tautoriieric iiiixtures of the two possible Corms. Their reaction Iwoducts arc not ncccssurily obtained in equal parts but in proportions wliicli differ froiii eonipound to conipound. The ratios of isomers resulting froni the metliylation of u number of iinidazoles under a variety of experiinental conditions are given in Table XV. It will 1)c noted that the nature of the suhstituents on tlic ii~idazolcring and also the experimental conditions uscd, litivc a pronounccd effect on the course of the reaction. Elcctronegtttivc sulwtitucnts. suc*li as tlic nitro group. halogen, the carhoxy group or tlic nldclipdc groiip, d i w t tlic methyl grorrl) predominantly to the adjacent iiitrogcn ntoiii wlicn iiictliyl sulfate is usctl as the alkylating agent. The dirccting inflwwc of electroncgativc subt oiiicric

stituents is less pronounced when irictiiyl sulfate and alkali are employed in the alkylation. The methylation of imidazoles with methyl iodide via the silver salts leads in many instances to entirely different results. The pronounced effect of certain substituents on the tautomeric behavior of the imidazoles is little understood, and speculation on this point would seem premature since the experimental material at hand is rather limited. The highly asfiociated character of the imidazoles may tx connected with their tautomeric behavior. In Section D-2these association complexes were formulated as hydrogen-bonded macromolecules. The interaction of such a complex structure with a given reagent may give rise to the formation of isomers and thus simulate intramolecular tautomerism. Such a mechanism may be operative in non-polar solvents only, since association is negligible in polar solvents. TABLE XV. Ratios of Isomers Formed on Methylation of Imidaaoles under Varying Conditions" Methylation pwcediire LfelSO4

Compound

hfe&Or

and alkali

A g salt

with Me1

Disaomethane

Refu

4(or 5)-Methylimidaeole. . . . . . . . . . . 1 :2.2b 4(or 5)-Cyanomethyl. . . . . . . . . . . . . . 1:6 4(or 5)-Phengl-. . . . . . . . . . . . . . . . . . . 4(or 5)-Bromct. . . . . . . . . . . . . . . . . . . 34:I. 4(or 5)-Nitm.. . . . . . . . . . . . . . . . . . . 350:1 4(0r 5)-Ndro-%methyl-. ........... 50: 1 4(or 5)-ivilr&(or 4)-methyl-. . . . . 233: 1 4(or 5)-ivdro-5(or 4)-bromo-. ....... 1,5* 4(or 5)-Ndro-5(or 4)-(pnitrophenyl)1,5* 4(or 5)-Bf&(or 4)-methyl-. ..... 1,5* 1,5* 4(or 5)-&omcr-5(or 4hphenyl- ...... 4(or 5)-Nilr&(or 4)-methyl-%brom+ 1 ,5* 45: 1 2,4(0r 2,6)-DibomA(or 4)-methyl-. 4(or 5)-Nitw5(or 4)-styryI-. ....... 4(0r 5)-Imidezolecarboxaldebyde.. .. 1 ,5* 4(or 5)-Methylb(or 4)-imidazolecar1,5* boxaldehyde.................... Methyl 4(or S)-imidaaolecarboxylate. 1,5* Methyl .G(or 6)-zitr&(or 4)-imidazolecsrhoxylate ............... 4(or 5)-Nilm5(or 4)-imidazolec~rboxamide ................. : .....

-

-

The 6guree represent the ratios of the 1,5 to the 1,4 isomers. Starred figurw

(*) indicate the preaence of only one isomer. The dmipation of the isomers in the

0

disubstituted imidazoles is b a d on the relative position of the italicized substit uent and entering methyl group. * Methylation with methyl iodide in benzene.

30

Chemist.ry of Classes and Derivatives

It seems more plausible t.hat prototropic changes of the type illufitrated are involved, especially since both tautomers are derivable from common ions.

H

Although it is not possible at present to account fully for the tautoineric nature of the imidazoles, there seems to be little doubt that this phenomenon is due to intermolecular reactions between two or more molecules. It does not involve the intramolecular shift of a proton from one nitrogen to the other, as visualized by earlier investigators.

Bibliography 1. Debus, H., Ann. 107, I!N (1858). 2. Hbnbsch, A., &id. 9.19, 1 (1888).

3. Huckel, W., Datow, J., and Simmerebadi. E.,2. p h p . Ctcern. lS6A, 129 (1940). 4. Goldschmidt, H., Rcr. 14, 1844 (1881). 5. Wallach, O., An.%.214, 309 (1882). 6. Hunter,L., and Marriott, J. A., J . Chem. SOC.19&, 777. 5. Jensen, K. A., and Friediger, A., Ygl. Danske Videnskab. Selskab, Mul. jvx. Medd. 20 (No.20), I (1943). 8. Hunter, G., Biochent. J. ,$O, 1183 (I=). 0. Cavalieri, L. F., Bendich, .\., Tinker, J. P.,nnd Brown, G. B., J. Am. Cliem. Soc. 70,3815 (1918). 10. Kohlrausch, K. W. F.. and Sckn, R.. Ber. 71, 985 (1938). 11. Radziscewski, B., ibid. 10, 70 (1877). 12. Traatz, M., &. p h p Chrm. 5?.((6 (lm5). 13. Weiser, H. B., J . phys. C h ~ n i22, . 439 (1918). 14. Rhatnagar. S. S., and Mathur, K. G., 2. phys. C h . 169A. 454 (1932). 15. Cottman, E. W.,Moffett, R. B., and Moffett, S. M., Proc. Indint~rA c d . Sci. 47. 124 (1937). 16. Cook, A. H., and Jon-,

D.G.. J . Chem. &c. IS41,278. 17. von Auwers. K..and Ern~t.W.,2. phu8. Chom. 1%. 217 (1E6). 18. Heller, G., Ber. 37, 3112 (1904). 19. Gerngrw, O., ibirf. 46, 1908 (1913). 20. Parrod, J., Ann. chim. phyx. 1.9. 205 (1933). 21. Leiter, L., J . B i d . Chem. 64. 125 (1!325). 22. Fargher, R. G.,and Pyman, F. L., J . Chrm. Pnr. 115, 317 (1919). 23. Pnrrod, J., Bull. snr. chini. Fmnre 61, 1424 (1932).

.

I. General Properties and Structure of Imidamles 24. John, W., Bet. 68, 2283 (1935). 25. Redemann, C. E., and Niemann, C., 1. Am. Chem. SOC.69,690 (1940). 26. Langley, W. D.,and Albrecht, A. J., J . Bwl. Cltem. 10% 129 (1935). 27. Frey, 2. S., Compt. rend. roS, 759 (1939). 28. Frey, Z.8, Ann. chim. phus. 18, 5 (1943). 29. Horn, F., 2. physiol. Chem.2m,111 (1932). 30. Dedichen, G., Ber. .W,1831 (1908). 11. Wallach, O., aid. 26, 644 (1882). 32. Kirby, A. H. My and Keuberger, A , Bwchem. J . 32, 1146 (1938). 32a. Cowgill, R. W., and Clark, W. M., J . Biol. Chem. 198, 33 (1962). 33. Brown, H. C., and Barabae, G. K., J . Am. Chem. SOC.69, 1137 (1947). 34. Forayth, W.G., and Pymsn, F. L., J . Chem. SOC.137, 573 (1925). 35. Hazeldine, C. E., Pyman, F. L., and Winchester, J., axd. fS,1431 (1924). 36. Windaue, A , and Knoop, F., Ber. 88,1166 (1905). 37. Feigl, F.,and Gleich, H., Monakh. 49, 385 (1928). 38. Oddo, B., and Mingoia, Q., Gmz. chim. ital. 68, 673 (1928). 39. Oddo, B., and Mingoia, Q., W.68,684 (19as). 40. Weidenhagen, R., and Remnann, R, Ber. 68, 1963 (1936). 41. Strain, H. H.,1. Am. Chem. Soc. 49, 1995 (1927). 42. Wyss, G, Bet. 10, 1385 (lS77). 43. Hartmann, M., and Panierllon, L., Helu. Cirim. Actn 91, 1692 (1938). 4-1. Weidenhagen, R., and Wegner, H., Ber. 71, 2124 (1938). 45. Winans, C. F., and Adkina, H., 1. Am. Chem. SOC.66, 4167 (1933). 46. Waser, E., and Gratsos, A., Hela. C h h . Acta 11, (1928). 47. Radzieeedi, B., Ber. 17, 1289 (1884). 48. Pinner, A., and Schwam, R., aid. 86. 2441 (1902). 49. Botwinnik, M. M., and Prokofjev, M. A., J. prnkf. Chem. 1.48, 191 (1937). 50. Laurent, A., ibict. 36, 455 (1845). 61. Radakeewaki, B., Ber. 16, 1 4 s (1882). 52. Fischer, E.,and Troechke, H.,ibid. 13, 708 (1880). 63. Japp, F. R., and Robinson, H.H.,ibid. 16, 1288 (1882). 54. Japp, F. R.,&id. 26, 2410 (1882). 55. Bamberger, E., Ann. ZJ3,267 (1893). 53. Pauling, L.,and Sherman, J., J. Chem. Phys. I , 606 (1933). 37. Schomaker, V.,and Pauling, L., J . Am. Chem. Soc. 61, 1769 (1939). 58. De Vries Robles, H .,Rsc. tmu. h i m . 6S, 111 (1939). 59. Hill, T.L.,and Branch, G. E. K.,SciencS 91, 145 (1940). 60. Wiegand, C., and Merkel, E., Arm. 667,242 (1947). 61. Gabriel, S., and Posner, T.,Ber. 27, 1037 (1894). 62. Jianecke, E., ibid. 39, 1095 (1899). 68. Minovici, 8. S.,ibid. 99, a097 (1896). 64. Kunckell, F., &id. 34, 637 (1901). G5. Burtlee, R, and Pyman, F. L., J. Chem. Soc. I B , 361 (1923). 66. Pyman, F. L., &id. 97, 1814 (1910). 67. Pyman, F. L.,&id. ldf, 2616 (1922). 68. AUsebrook, W. E., Gulland, J. M.,and Story, L. F., ibid. 1949, 232. 09. Hubball, W., and Pyman, 8'. L.,ibid. 1928, 21. 70. Pyman, F. L., aid. M,2172 (1911). 71. Sakami, W., and Wileon, D. N.,J. BWZ. Chem. 164, 215 (1944). 72. Bhagwat, V. K.,and Pyman,F. L.,J . Chem. Soc. 1157, 1832 (1925).

31

This Page Intentionally Left Blank

CHAPTER I1

The Alkyl- and Arylimidazoles A. Synthetic Procedures 1. Introduction

In addition to their usefulness for the preparation of alkyl- and arylimidazoles, some of the procedures described in this section have been successfully applied to the synthesis of imidaaoles containing additional functional groups or heterocyclic substituents. It seems appropriate to summarize them in the present section because their widest application lies in the preparation of alkyl- and arylimidazoles. 2. The Radziszewskl Synthede

An imidazole synthesis involving the condensation of a dicarbonyl compound with an aldehyde and ammonia was discovered almost simultaneously by Japp (1) and Radziszewski (2). The former investigator reacted benzil with p-hydroxybenzaldehyde and ammonia, and obtained 4,5-diphenyl-2-p-hydroxyphenylimidazole;while the latter prepared 2,4,5-triphenylimidazole (loyhine) by reacting benzil with benzaldehyde and ammonia. The method carries Radziszewski's name because he ex-

q

=

o

(3\

CEO

-

+"".O=x-j NHs

3/ \

N

Lophine

tended it t o the preparation of simpler imidazoles and demonstrated its general applicability. It occurred to him that the formation of imidazole from glyoxal and ammonia, as discovered by Debus (3), might proceed in a manner similar t o the lophine synthesis, imidazole formation being due to tlie interaction of (tiiiiuonia, glyoxal, and foriiialdehydc. The formaldehyde, he reasoned, might arise from the cleavage of the glyoxal

33

34

Chemistry of Classes and Derivatives

under the influence of ammonia. In order to test this hypothesis he reacted a mixture of glyoxal and ammonia with a number of aldehydes and aldehyde ammonias, and obtained 2-substituted imidazoles (4-7). The 2-substituent in the imidazoles was representative of the aldehyde employed. The Radziszewski synthesis has found some use in the preparation of substituted imidazoles (8-12). H

The condensation of an a-kctoaldehyde with ammonia and formtrldehyde leads to the formation of a 4(or 5)-1nonosubstitutcd imidazole. Examples arc the formation of 4(0r 5 )-methyl- and of 4(or 5 )-phenylimidaeole from methyl- and phenylglyoxal and formaldehyde (13-15). The formation of 2,4 (or 2 3 ) -dimethglimidaaole from methylglyoxal and acetaldehyde represents an example of the combination of a n a-ketoaldehyde with a higher aldehyde (13). An a-diketone may be combined with formaldehyde or a higher aldehyde to give either a 4,5-disubstituted or a 2,4,5-trisubstituted imidazole (16). The conventional method for bringing about these condensations involves the use of alcoholic ammonia. This older technique is highly unsatisfactory in many instances, since the desired imidazoles are obtained in relatively small yields. Negligible amounts of 4,5-diphenylimidazole are realized from the reaction of benzil with formaldehyde in ethanolic ammonia (15,17). On the other hand, almost quantitative yields of this compound result when the condensation is carried out in glacial acetic acid, with ammonium acetate as the source of ammonia and hexamethylenetetramine as that of the formaldehyde (18). Replacement of the hexamethylenetetraniine by paraldehyde, acetaldehyde, propionaldehyde, isobutaldehyde, salicylaldehyde, and anisaldehyde affords excellent yields of the corresponding 2-substituted 4,5-diphenylimidszoles. Acrylaldehyde, crotonaldehyde, and cinnamaldehyde fail to give imidazoles (19). Substitution of the conventional alcoholic ammonia by glacial acetic acid and ammonium acetate represents a distinct improvement over the older technique (18). The formation of lophine (IV) from benzil (I), ammonia, and benzaldehyde may involve the production of a diamine intermediate (11),its condensation with banzil yielding a product of structure (1111, followed by a rearrangement (lS,20).

11. .41kyl- and Arylimidamles

35

(IV)

The ammonolysis of beneil under a variety of experimental conditions results in the formation of lophine (21-26). Practically quantitative yields are realized when the diketone is subjected to the action of ammonium acetate in glacial acetic acid (18). The reaction between benzil and ammonia in alcoholic solution affords mainly three products, N-desylbenzamide, 2,4,5-triphenyIoxazole, and 2,4,5-triphenylimidazole (lophine).

N-Desylbenzamide

2,4,5TriphenyloxazoleIe

2,4,5Triphenylirnidarole

N-Desylbeneamide seems to be the precursor of the other two compounds. Its formation from bemil and ammonia may proceed as in equation (1), page 36. Once formed, the N-deaylbeneamide-may either undergo cyclodehydration with the formation of 2,4,5-triphenyIoxazole, or it may react with ammonia to give lophine. The latter reaction occurs very readily upon treatment of N-desylbenzamide with ammonium acetate and glacial acetic acid. N-Desylformamide and N-deaylacetamide give 4,5-diphenylrespectively, in practically imidaeole and 2-methyl-4,5-diphenylimidaeole, quantitative yields when exposed to the action of ammonium acetate in glacial acetic acid (1837). See equation (2), page 36. An alternative explanation for the formation of the various products resulting from the ammonolysis of bemil was formulated by Japp (24). He postulated the reaction as an initial fission of a molecule of benzil, with the formation of a molecule of benaaldehyde and a molecule of either

Chemistry of Clnsses and Derivnt.ivre

36

W

R- H, or CHI ctliyl tjcnzoatc or bcnzttmiclc. Tlic conhination of the l)enzultleliyde with aiii~noniaand snotlicr ~riolcculcof IBcnzil ttwourita, :wortling to this view, for tlic foritiirtion of t Iic lopliinc. The smnronolyais of hcnzil rcprcscnts a coiiiplcs rwvtiori, :inti I)ot11 j):itlnviiys i i ~ opcrntc y siiii~ilt:irii!o~isl~. ITndcr tlw influcncc of :uiiiiioniit, cii:wctyl is t r:uirfoiwictl into 2,4,5t riii~ctliyliiiiidszolc (28,29,46) . \\'lictliw iiiiirLrzolc foriiiat,ioii is in this (*tts(i the rwult of elcan-agc of tlic t1i:tc~tylinto acrtaiiiidc anti :icc~t:rlrlcliydc, tlic I:it.tcr rinrlergoing iiiii~latzolc for1ii:rtioii with :i scc*ontl iiioicciile of rliscctyl, or wliet.licr iL iiirchmisiii s i i i i i l w to t l i v on19 ciisviissccl in tlic caw of henzil is involved, rriiiains to I)(! cliwidwted. Sniall amounts of 2-iiicthpl-4,ii-ctipilien~limid;laolcrcwilt frola tlic interaction of Imzoin with tiiniiiotiiiiin acctstc in glacial acetic acid (27). The major products of this reaction arc ainarone and dihydroamarone.

11. Alkyl- and Arylimidazoles

Amarone

Dihydrosmarone

37

IEMethyl4,bdiphenylimidasole

The formation of these products may proceed through the desylamine and N-desyiacetamide stages as shown below. Self-condensation of the desylainine may afford dihydroamarone, which undergoes dehydrogena-

/

tion to give arnaronc. As has been stated above, interaction of the N-desylacetamide and animonia gives 2-methyl-4,5-diphenylimidszole. In the presence of formic acid, this sequence of reactions leads to the forination of 4,5-diphenyliaiidazole, aiiiaroxie foriiiation being negligiblr under tliese conditions. N-1)euylfolniwiiide sreiiin to I ) e the key interiiiediate in tlie process (27). Although tlie Rsdeiszewski synthesis has been applied to the preparation of a variety of iniidazoles, it is rat.her limited in scope. One of its

38

Chemistry of Clssses and Derivativa

serious limitations lies in the daculty in obtaining the necessary starting materials, especially those required for preparation of the more complex imidazoles. Also, in many instances it affords poor yields, and very frequently leads to the formation of mixtures of imidazoles which are difiicult to separate. 3. The Weidenhagen Synthesis

Weidenhagen developed an imidarole synthesis representing a great improvement over the older, Radziszewski method (30-32). This procedure is based upon the observation that a-hydroxyketones under the influence of ammoniacal cupric acetate solutions are quantitatively oxidized to the corresponding dicarbonyl derivatives. Carried out in the presence of an aldehyde, this process results in imidazole formation. The reaction may be visualized as occurring through the following sequence of steps. The cupric ion first oxidizes the hydroxyketone to a ketoaldehyde or a diketone, and thereby is converted into cuprous ion. The dicarbonyl compound under the influence of the ammonia condenses with the aldehyde, thus producing an imidazole which precipitates from the reaction mixture in the form of a sparingly soluble cuprous complex. Decomposition of this salt by means of hydrogen sulfide yields the free imidazole. Carried out in the presence of mineral acids this decomposition leads to the formation of the respective imidazole salts.

In practice, mixtures of the reactants are usually heated for a short time, whereupon the cuprous complex of the imidazole separates. The salt is collected, washed, and decomposed, giving the free imidazole which is obtained in a high degree of purity. The acetyl derivatives of hydroxyketones, or, in some cases, the corresponding a-halogenoketones, may .be substituted for thc hydroxyketones. The ammonia causes hydrolysis of

11. Alkyl- and Arylimidazoles

39

these substances to the hydroxyketones which, in turn, undergo oxidation and imidazole formation. For example, 4 (or 5) -methylimidazole may be prepared from hydroxyacetone acetoxyacetone, or chloroacetone.

B Acyloins may also serve as starting materials (33,34). Compounds such as acetoin, benzoin, or furoin undergo imidasole formation on treatment with an aldehyde and ammoniacal cupric acetate solutions. The formation of 2,4,S-t.ri-(2-furyl) imidasole from furoin and furfural demonstrates that even highly sensitive aldehydes may serve in this synthesis. The simplicity of operation, and the high yields usually obtained, characterize this imidazole synthesis as a most useful procedure. The iiw of a rather mild oxidizing agent allows the introduction of sensitive groups into the starting materials prior to their conversion into imidazoles. Formation of undesirable side products (resulting from the self-condensation of the dicarbonyl compound) represents a disadvantage of the method. Such side reactions become prominent when higher, leas reactive aldehydes are employed. The procedure is thus not applicable to the preparation of imidazoles containing higher aliphatic suhstituents in the 2-position. 4. Formation from Carbohydrates

The formation of 4(or 5)-methylimidasole from D-glucose under the influence of zinc hydroxide and ammonia was discovered in 1905 by Windaus and Knoop (35). This reaction captured the interest of chemists, since they expected that study of this transformation might aid in clarification of the biosynthesis of the imidazole ring. I n their first experiments, Windaus and Knoop (35) added zinc hydroxide and ammonia to a solution of *glucose, and kept the mixture at room temperature for six weeks. The resulting insoluble zinc salt wan

collected, decomposed with hydrogen sulfide, and 4(or 5 )-methylimidazole way isolated as the oxalate. D-Mannose, D-fructose, L-sorbose, D-xylotle, and L-arabinose also yield appreciable amounts of 4 lor 5)-methylimidazole under similar conditions, while maltose, lactose. and n-galactosc afford only traces of the compound (36,311. Important, to elucidation of thc intermedintc steps in this rewtioli is the observation that the addition of acetaldehyde to the reaction niixtuw leads to the forinat.ion of L inixturc of 4(0r Ti)-methyl- and 2,4(or 2,5)dimethylimidazole. The addition of formaldehyde increascs the yield of 4(or 5)-methylimidazole (38). There is ample evidence (13,14,39) to substantiate the view, first expressed by Windaus (351, that the initial step represents a breakdown of the D-glucose molecule with the formation of methylglyoxal. The methylglyoxal thus formed reacts with ammonia and formaldehyde to yield thc final prodmts (Radziszewski synthesis) The following observations support this scheme: (I) methylglyoxal reacts with zinc hydroxide plus ammonia and formaldehyde to give 4(or 5 ) methylimidasole ; ( 2 ) the reaction of methylglyoxnl wit 11 acctnldehydc plus zinc hydroxide and ammonia affords 2,4(or 2,s)-tliinetliyliinidazole ; (3)methylglyoxal can be isolated from tlic D - ~ ~ U C O S zinc C hydroside-minionia reaction mixture in tlic form of its p-nitrophcnylosazonc or its tlisemirarbazone. Tlic finding that mctliylglyoxrtl fails to give 4(or 5 )iiiethylimidazole on treatment with zinc liydroxide-nmiiionia slio~rsthat it, cannot, be the source of the formaldehyde. Thc reaction wliicli leads to the forination of 4(or 5 ) -inetliylimidrteolc froin gliirow iiisy tlws he

Isolation of a mixture of 4(or 5)-methyl- and of 2,4 (or 2,s) -dimethylimidazoles from the reaction of ~-rhamnosewith zinc hyrlroxide-ammonia indicates a breakdown of this sugar into methylglyoxal plus a mixture of acetaldehyde and formaldehyde. Thc interaction of these compounds would be expected t o afford the observed mixture of imidazoles (40). The transformation of D-glucose into 4(or 5 ) -methyliniidazole by the above procedure represents one of the most convenient methods known for the

11. Alkyl- and Arylimidazoleu

41

preparation of this imidazole. The reaction time may be greatly shortened and the yields increased, if the synthesis is carried out a t 100°C. rather than a t room temperature (13). 5. Formation from 2(3H)-ImidazoIethiones and Mthiohydantoins

One of the most important routes to alkyl- and arylimidazoles involves the desulfurization of alkyl- or aryl-2 ( 3 H )-imidazolethiones. These reH I R-YNY-S R’-C-N 1

I

.c-

H

H I R-C‘ N‘7-SH H

R’-C-N

I

H

I R - p p i R‘-C-N

actions will be treated in connection with the discussion of the 2 ( 3 H ) imidazolethiones (see Chapter 111, Section A-3-d) . The availability of a great variety of 2(3N)-imidazolethiones, and the ease with which they are convertible into imidazoles either by oxidation or by hydrogenolysis, make t.liis method one of the most important synthetic tools in the imidasole field. I n this connection, it is of interest to note that treatment with Raney nickel brings about the conversion of dithiohydantoins into imidazoles (41,B). In contrast to the procedures previously dis-

42

Chemistry of C l m and Derivatives

cussed, these syntheses are not applicable to the preparation of imidazoles containing substituents in the 2-position. 6. Formation from ImidszolecarboxylicAcids

Many 2-alkyl- or 2-awl-substituted imidazoles cannot be satisfactorily prepared according to the Raciziszewski method. These imidazoles are available through the decarboxylation of suitably substituted 4,5-imidazoledicarboxylic acids, prepared according to the Maquenne procedure (43) (see Chapter VI, Section A-4). Decurboxylation niay be effected by heating tlic conipounds above their melting points, or by reflwing their aniline solutions. The moat convenient procedure for the preparation of imidazole involves the decarboxylation of 4,5-imidszoledicarboxylic acid, in the presence of LI copper-chroniiwn oxide catalyst (44-48).

B HOOC-~HNY-R HOOC-C-N

A

- 2coa

H-CHNY-R

H-LN

7. Formation from 2-Imldazolinea

2-Imidarolines have served as the starting niaterials for the prepasstion of I-mono- or 1,2-dialkylimidazoles (49). Aroinatization of the ring is effected by dehydrogenation with nickel hydrogenation catalysts in the liquid phase at a temperature of 300°C. This method, although excellent for the preparation of certain alkyluted irnidazoles, docs not seem applicable to the preparation of more complex irnidazoles bccausc of the rather drastic conditions used to bring about the dehydrogenation.

In contrast to the alkyliniidazolineu (which require rather drastic conditions for their conversion into imidazoles) , certain arylitnidazolines are transformed into arylimidazoles with remarkable ease. Amariric . (2,4,5-triphenyl-2-imidazoline)is an outstanding example. It is quantitatively converted into lophine (2,4,5-triphenylimidarole) when iodine or potassium amide are added to itu solution in liquid ammonia (2OOpO). Mild oxidation with chromium trioxide in acetic acid also brings about the conversion of amarine into lophine (51-53).

11. AIkyI- and Arylimidazoies

43

8. Miscellaneous Procedures

In addition to the previously mentioned, generally applicable procedures, there are a number of other methods which have been used to prepare imidazoles. One of these reactions involves the interaction of benzamidine with an a-halogenoketone. This method has been successfully applied to the preparation of 2,4(or 2,5)-diphenylimidazole and to the synthesis of 2-phenyl-4(or fi)-rnethylimidrtaolr: iA4$5).

R-

-

X halogen

The formation of lophine by the interaction of benzoin with benzamidine also belongs t.o this class of reactions (56).

The reaction between an a-aminonitrile and an aldehyde may result. in thc formation of an imidazole. An example of this reaction is the formation of 2,4 (or, 2,5) -diyhenylimidazole from a-aminobenzyl cyanide and benzaldehyde (57).

The condcnsation of an a-aminoketone hydrochloride with an imiioether produces a mixture of an oxazole and an imidasole (55). The exposure of oxszoles to aqueous ammonia at high temperatures may residt in imidazole formation. The first conversion of an oxazole into an imidazole was reported as early as 1888 by Lewy (58), who transformed 2-methyl-4-pheny loxazole into 2-methyl-4 (or 5) -phenylimidazole+ (59) *"him compound is recorded in Beihein's Handbilch (4th ed., Vol. B,p. 190) aa %phenyl4(or Fi)-methylimidarole, but later NRS shown to be 2-methyl4(or S)-phenylimidazoIe (55,591.

44

Chemistry of Classes and DerivaEived

by trcutiiig the compound wit,ll aqucous aniaionia at 220-230" for sixteen hours. 2,5-Diphenyloxazole is converted into 2,4 (or 2,5)-diphenylimid-

mole under similar conditions (57). These conversions give poor yields, and offer little advantagc as prel)artttivc mcthocls. It is of interest to note, however, that alkyl- ;ind :~iyloxazole-4-carboxylicacids nrc converted in good yields into alkyl- and arylimidazoles when heated with aqueous ammonia a t a temperature of 150°C. Coinpounds such as 2-methyloxazole-4-carboxylic acid or 2-n-amyloxazolc-4-carboxylic acid afford 2-methyl- and 2-n-nmylimidazole, respectively (55,60). Thc carboxyl group facilitates the replacement of the ether oxygen by the imino group, possibly through the following elcckronic mechanism (55). The preparation of 2-plienyl-4 (or 5 )-ii~eth?rliniidszoleby smmonolysis p"

R-5"F-R' N-C-H

1

R" I -C0Ny - R '

I- COZ

of the readily available 2-phenyl-5-mcthyloxazolc-4-carI~oxylic*:wit I represents a convenicnt routc to this compound. A number of procctlurcs cq)cciaIly suitcd to thc prepttrtrtion of lopliiliv (2,4,5-triplienyli1~iid~~zolc) a n d of lopliinc derivatives deserve inention a t this point. Lophine is fornicd when liydrobcnattinide is lieated at 300°C. This reaction, which was investigated by Laurent in 1845, led to the discovery of lophine (15,61,62). Amarine (2,4,5-triphenyl-2-imidazoiine)represents an intermediate, and it becomes the major reaction product when hydrobenzamide is heated at 12.5-130°C. (63-67),or, preferably, when

11. AlkyI- and Arylidazoles

45

potassium ainide is added to a solution of hydrobenzamide in liquid ammonia (20). This conversion of hydrobenzamide into amarine may by a reaction involve the initial formation of 2,4,5-triphenyl-3-i1nidazoline coinparable to that leading to the production of benzoin from benzaldeliyde. Through a rearrangement, the 2,4,5-triphenyl-3-imidazoIine changes into the more stable amarine (20). The pronounced tendency of amarinc to undergo dcliydrogenation to lophine has been mentioned.

The conversion of 2,4,6-triplienyltriaeine (kyaplienine) into lophine by reduction with zinc dust in acetic acid was discovered by Radziszewski (2). The formation of 2!4,5-triplienylimidazoles from 2,4,64riphenyltriazines is a general reaction and represents a useful procedure for tlic preparation of substituted lophines (19j. The reaction kyapheninee lophine is reversible; the addition of iodine to a solution of lophine in liquid ammonia leads to the forinatiou of kyaphenine (20). A possible scheme for these convcrsions is shown in equation ( l ) ,page 46. Treatment with aqueous ammonia a t 200-230O converts N-desylbenzsnilide into N-phenyllophine (1,2,4,5-tetraphenylimidazole)(68,69). See equat.ion (2), page 46.

B. Properties and Chemical Behavior 1. Genetal Properties

The slkyl- and aiylimidazoles possessing a free iiiiino hydrogen arc arnphoteric compounds forming salts both with acids and with metals; the picrates and acid oxalat.es represent. especially suitable derivatives belonging for cliaractcrization purposes. The alkyl- and a~-yli~tiidazoles to this group are solids exhibiting a high degree of chemical stability.

Chemistry of Classes and Derivatives

46

H

H

Lopliinc

2-

x13,

b

Jiyaphcninc

Their chemical behavior closely parallels that observed with imidasole, md requires little additional comment. The methyl-substituted imidaeoles :&reslroi~gcrbases tliun imidarole. The introduction of phenyl groups into tlic iiiiicitrsole nucleus weakens the basic oiiaracter and increases tlic pseudoacidic properties (see Table XlIl ) . Tlic rrlkyl- and arylimidazoles csliibit a positive Yauly reaction (scc Chapter V, Section 13) provided t h y coiituin a free imino hydrogen :~ndat least onc frec iuethine goup. Lophine (2,4,5-triphenylimidarole) deserves special comment as the oldest, and most carefully investigated, representative of the arylimidaaoles. The compound melts at 275O, distils without decomposition, and exhibits great chemical stability, especially under acid conditions. The addition of metals or metal aniides to its solution in liquid ammonia results in the formation of salts (70). These hydrolyze when dissolved in water with the formation of lophinc and a metal hydroxide. Exposure

11. Alkyl- and Arylimidazoles

.

47

to hydrogen iodide at 300" brings about a slow conversion of lophine into benzoic acid (71); treatment with sodium in alcohol leaves the compound unchanged (53). Catalytic liydrogenation over IVillsGtter platinum in glacial acetic acid transforms lophine into 2,4,5-tricyclohexy1-2imidazoline (72). This behavior is rather unusual, since the imidazole ring in most of the other alkyl- or arylimiduzoles is resist,nnt to catalytic hydrogenation even at high temperatures and pressures (73). Lophine in sodium hydroxide solution in the presence of air undergoes slow decomposition into benzoic acid and anunonia; the process is accompanied by chemiluniinescence (62) (see Chapter I, Section B-7-43). Drastic oxidation with chromium trioxide in glacial acetic acid affords a mixture of benzeinide and dibenzamide (52). The direct nitration of lophine with

concentrated nitric acid at the boiling teuiperature results, in the formation of 2,4,5-triS(p-nitrophenyl)imidazole, a compound which exhibits considerably less stability toward alkali than does lophine (74).

2. Acylation

The observation that the simple iniidazoles are not readily acylated (75) is not too surprising if it is remembered that the irnino group in thc?iC compounds possesses the acidic character associated with a pyrrole nitrogen and not the basic properties of a secondary amino group (see Chapter I, Section C-2). The'study of the acylation of imidazoles is complicated by the property of a number of these substances to undergo ring fission under the influence of scylating reagents and alkalis. Under very carefully controlled experimental conditions, however, it is possible to obtain N-monobcnzoyl derivatives (76). Imidazole, 4 (or 5 ) -methylimidazole, 4,5-climet~1iylimidazoleJand methyl 4 (or 5 ) -methyl4 (or 4) -

Chemistry of Classes and Derivatives

88

imidazolecarboxylate form the corresponding N-benzoyl derivatives when two moles of base are reacted with one mole of benzoyl chloride in benzene solution. The second mole of base serves as the acceptor of the Iiydrochloric acid formed during tlie acylation reaction. The N-benzoyl derivatives are crystalline, low-melting compounds which undergo hydrolytic debenzoylation on exposure to moist air with the formation of the benzoic acid salts of the respective imidazoles. The henzoylation of imidazoles according to the Schotten-Baumann reaction does not usually result in the formation of N-benzoyl derivatives but brings about the fission of the imidazole ring. This reaction was discovered during attempts to benzoylate benzimidazole, and, in recognition of its discoverer, is frequently referred to as the Bainberger reaction (77). The reaction of imidazole with benzoyl chloride and alkali a t low temperature results in the formation of 1,2-diLenzamidoethylene and formic acid (78,79). Tlie intermediate steps leading to the ultimate cleavage of the imidazole ring have been investigated with benzimidazole and will be discussed in Chapter VIII, Section D. The 1abilit.y under the conditions H

I

H-c.N-(;-H II H-C-N

H

H-F

H-C-N-CO

+ HCOO-

H

of the Scliotten-Bauiuann berizoylatioii of the otherwise liiglily stable imidazole ring is remarkable indeed. The ability t20 bring ntmut t,lw rupturc of the iinidazole ring is not limited to benzoyl chloride. Thus 4 (or 5)-metliylimiduzole is converted I -~)ropcnc and formic acid when it is into 1,2-di-isovaleryla1i~idoshaken with isovaleryl cliloridc in the presence of sodium hydroxide (80). The reaction of imidazole iiiagnesium bromide with benzoyl chloride also results in ring fission with the forination of 1,2-dibenzamidoethyIene (81). Acetic anhydride in tlie presence of sodium acetate fails to bring about cleavage of tlie iniiduzole ring (80,82). Tlie property of undergoing ring fission on trcatnicnt with benzoyl chloride and alkali is not common to all the imidazolcs. Alkyliniidazoles such as 4 (or 5 )-methyl-, 4(or 5 )-ethyl-, or 4,5-di1iietliyliiiiiclazoleundergo cleavage (83,84), while the N-dkylimidazoles resist the action of bcnzoyl chloride and alkali (85,86). Electronegat,ivc sul)&t,ucnt,s on tltc ring ] " ~ e n t .the fission process: sucli rompoiiiids as 4 (or 5 )-nitwilnidnzolo (B), 4(or S)-imi-

11. Alkyl- and Arylimidszoles

49

dazolecarboxaldehyde (SO), or 4 (or 5 ) -imidazolecarboxylic acid (87) remain unchanged when they are subjected to the action of benzoyl chloride and alkali, while 2-phenyl- and 2-p-nitrophenylimidazole are converted into their N-benzoyl derivatives (88). The benzoylation of 2,4,5-tribromoimidazole also results in the formation of a N-benzoyl defivative (89). The above-mentioned 1,2-dibenzamidoethyIene derivatives may serve as the starting materials for the preparation of 2-substituted imidazoles. The reaction of 1,2-dibenzainido-l-propene with propionic anhydride a t 180" results in the formation of 2-ethyl-4(or 5 ) metliylimidazole, whilc its rcaction with acctia anhydride affords 2,4( or 3 5 ) -dimet hylimidwiole (90).

Imidazole and its alkyl derivatives fail to undergo C-acylation in the presence of acyl chlorides or acid anhydrides and aluminum chloride. In this respect they behave like pyridine, wliiah also fails to undergo the Friedel-Crafts reaction. 3. Alkylation

The first observation of the replacement of the imino hydrogen of imidazole by alkyl groups was made by Wyss (75). He prepared N-ethylimidazolium bromide and N-benzylimidazolium chloride by the treatment of imidazole with ethyl bromide and benzyl chloride, respectively, and iiberated the corresponding free alkylimidaeole from these salts by treatment with silver oxide. Further studies (7,91-95) have

amply demonstrated that imidazoles containing a free imino group readily undergo N-alkylation under a variety of conditions. Reaction with alkyl halides followed by treatment with alkalis or interaction of their silver salts with alkyl halides are good preparative methods. Imidazoles react with dimethyl sulfate or diazomethane to give N-methyl derivatives (49,86,95-101).

Clicmistry of Classes and Derivat.iws

50

'I'he N-alkyl- and nrylimidazoles arc basic suhstaims since they have lost the pseudoacidic properties associated with the imino hydrogen. They are highly stable, distillable liquids, and form crystalline salts with acids. The picrates and chloroplatinates are well suited for characterisation purposes. The marked changes in physical behavior which accompany the -1'-alkylation have been mentioned previously (see Chapter 'I 1 . Rather interefiting is thc behavior of l-met,hyliniidRrc,lc.. 'Phis cumpound undergoes R rearrangement with thc formation of 2-methyliinid;tzolc when it is passed through tb rcrl-hot tube (38,93). This rernlls the c11, I

H-C-N

A

€I I

-cyNxf

-CH

H H-C-N

similar hchavior of N-methylpyrrole, which also rearranges with the formation of a C-methyl compound under similar conditions. The reaction is not successful with higher N-alkylimidaroles. I t is important to note that the bemyl group in N-benzylimidazoleu i w i he removed by reduction with sodium in liquid ammonia, resulting in regcnrration of the free imino group (102). This behavior of thc .V-hcnzylimidazoles is significant from the synt.hetic point of view. The N-monoalkylimidazoles have the ability to add a molecule of 311 d q - 1 halidc. with the formation of dialkylimidazolium salts. Two possible 1wys in which this addition may occur cnn be vimalixed. Either thc alkyl halidc adds to the non-nlkylated nitrogen with formation of R 1,3-dialkylimidazoIium salt (I),or it may combine with the suhstitatcd nitrogen, thas forming R 1.1-didkyIimidaxolinm salt (IT). Heating XR I

H -c " II H -C-N

~ -H

X-

011-

A

S = hrlogcn

R I

NIfz IICOO-

+

XI12 I

R'

II. Alkyl- and Aryhidazolea

51

one mole of such salts with sodimn or potassium hydroxide solution brings about a complete fission of the imidasole ring with the formation of two moles of primary amine and one of formic acid (85,91,103,104). This behavior of the quaternary salts shows that they are 1,3-dialkylimidasolium salts and not 1,l-dialkylimidazolium salts. A 1,l-dialkylimidasolium salt would not be expected to yield two moles of primary amine on decomposition with alkali. The intermediate steps leading to the disruption of the imidaeolium salts have not been studied in the case of the simple imidazoles, but have been well investigated in the 1,3-dialkylbensimidasoliumseries. It would seem logical to assume that similar mechanisms are operative in both instances and that the results obtained with the benzimidasoles (see Chapter VIII, Section E) are also applicable to the simpler molecules. When heated, the 1,3-dialkylimidaeoliu halides decompose into one molecule each of a N-inonoalkylimidasole and one molecule of an alkyl halide. The stability of the nitrogen-alkyl bond depends on the nature of the alkyl group and also on the character of other ring substituents. For example, 1-methyl-3-ethylimidazolium iodide affords 1-ethylimidasole and methyl iodide. l-Methyl-3-benzylimidasolium iodide dissociates

with the formation of 1-methylimidazole, the benzyl moiety leaving the molecule in the form of benzyl iodide (105-107). This finding is in general agreement with the observed ease with which the hensyl group is removed from other molecules. An electronegative substituent in the 4(or 5)-position of a 1,3-dimethylimidasolium salt weakens the adjacent nitrogen-alkyl bond. The 4 (or 5)-chloro-, bromo-, or nitro-] ,3-dimethylimidazolium iodides decompose with the exclusive formation of l-methyl-4-chloro-, bromo-, or nitroimidasoles,respectively. This reaction has preparative potentialities.

52

Chemistry of

Classes and

Derivatives

The influence of a phenyl group is less pronounced, as evidenced by the behavior of 1,3-dimethyl-4 (or 5 )-phenylimidazoliuin iodide. Heat decomposes this compound into a mixture of isomers containing a small amount of 1-methyl-5-phenylimidazoleand a larger quantity of l-methyl4-phenylimidaeole (106). Bibliography

1. Japp, F. R.,and Robinson, H . H.,Bet. 16, 1268 (1882). 2. Radziszewski, B., ibid. 16, 1493 (1882). 3. Debus, H.,Ann. Im, 199 (1868). 4. Radziszewski, B., Ber. 16, 2706 (1882). 5. Behrend, R.,and Schmitz, J., Ann. ,9777,310 (18%). 6. Radziszewski, B., and Seul. L., Ber. 17, 1291 (1884). 7. Radziszewski, B.,ibid. 16, 487 (1883) 8. Radziszewski, B., iba. 16, 747 (2883). 9. Karcz, M., Momtsh. S, 218 (1887). 10. Riegcr, 5.. i b 2 . 9, 603 (1888). 11. Windnus, A., and Vogt, W., BET.40, 3691 (IW7). 12. Jolin. W.,ibid. 64 2283 (1935). 18. Bernhnuer, K., Z . physiol. Chem. 183, 67 (1929). 14. Gulland, J. M.,and Macrae, T.F., J. Chenr. Soc. 10S9, W2. 15. Pinner, A., Ber. 35,4131 (1902). 16. Japp, F. R., and Wynne, W. P., J. Chena. Soc. 49, 462 (1886). 17. Japp, F. R.,ibid. 61, 557 (1887). 18. Davidson, D.,Weiss, M.,and Jelling, M., J. Org. Cheni. I , 319 (1837). 19. Cook, A. H., and Jones. D. G., J. Chem. Sor. 19.j1, 278. 20. Strain, H. H.,J . Am. Chcm. SOC.49, 1558 (1927). 21. Zinin, N.,Ann. 34, 186 (1840). 22. Lnurent, A., J. prokl. Clrcw. 36, 461 (1845). 23. Ilenius, M.,Ann. 237,339 (1885). 24. Jnpp, F. R.,and Wynnc. W. P., J . Clrena. SOC.40,473 (1886). 25. Struin, H.H.,J . Am. C1ir.n~SOC.69,820 (1930). 26. tcslic, W. B., and W:ii.l, C . W.,J . Orq. Chem.7 , W (1942). 27. Davidson, D.,Weiss, M., 2nd Jelling, M., ibg. 9,325 (1937). 28. von Pechmann, H., Ber. 21, 1411 (1888). 29. Fittig, R.,Daimler, C., and ICeIler, H.. Ann. $49, 182 (1888). 30. Weidenhagen, R.,and Herrmnnn, R., Bcr. GS, 1953 (1935). 31. Weidenhagen, R.,and Herrmnnn, R., 2. angew. Chem. 48,506 (1935). 32. Weidenhagen, R., and Rienacker, H., nsr. 7% 57 (1939). 33, Weidenhagcn, R.,Herrmnnn, R., and Wegner, H.,ibid. 70, 570 (1937). 34. Bernhauer, K.,and Hoffmnnn. R., J. prakt. Chem. (2) 149, 321 (1937). 35. Windaus, A., and Knoop, F.. Bcr. $9, 1166 (19051. 36. Windaus, A., &id. 40, 799 (1907). 37. Iuouye, K.,&idd.40, 1890 (1907). 38. Windsus, A.,&id. M,3886 f 1906). 39. Sjollcma, B. J., and I b u , A. J. H., J