Carbene Protonation

Wolfgang Kirmse

I INTRODUCTION

Carbenes are neutral, divalent derivatives of carbon.1 The carbene carbon has two electrons not involved in bonding which can be spin-paired (singlet state) or unpaired (triplet state). The electron pair of a singlet carbene can accept a proton (or other electrophile) with formation of a carbocation (Scheme 1). Current nomenclature defines carbenium ions (trivalent carbocations) and carbenes as acid-base pairs,2, 3 although the generic names were devised from a different perspective (the name carbene was coined to fit a carbon with the same degree of "unsaturation" as an alkene).4

For years, the acid-base relationship of carbenium ions and carbenes was regarded as a purely formal concept which would not materialize. However, experimental verification was foreshadowed by Breslow's pioneering work on the mechanism of thiamine action.5, 6 It was observed that imidazolium (1a) and thiazolium salts (1b) exchange hydrogen at C-2 for deuterium under extraordinarily mild conditions.5a, 7 Base converts 1 into a carbene dimer 4 which reverts to 1 on treatment with acid (Scheme 2).8 Although these processes are likely to be mediated by 2 and 3, the protonation of 2 was conclusively demonstrated only after the advent of persistent, monomelic imidazolylidenes (see Section V).9

Suggestive evidence for the protonation of diphenylcarbene was uncovered in 1963.10 Photolysis of diphenyldiazomethane in a methanolic solution of lithium azide produced benzhydryl methyl ether and benzhydryl azide in virtually the same ratio as that obtained by solvolysis of benzhydryl chloride. These results pointed to the diphenylcarbenium ion as an intermediate in the reaction of diphenylcarbene with methanol (Scheme 3). However, many researchers preferred to explain the O–H insertion reactions of diarylcarbenes in terms of electrophilic attack at oxygen (ylide mechanism),11 until the intervention of carbocations was demonstrated by time-resolved spectroscopy (see Section III).12

As exemplified above, the chemistry of carbenes in protic media raised the prospect that carbocations could be formed. Experiments were designed to identify the intervening species by means of product and/or label distributions (Section II). The results thus obtained set the stage for the application of spectroscopie techniques, based on the laser flash photolysis (LFP) of carbene precursors (Sections III and IV). Some of the earlier work has been reviewed,13 in the context of O–H insertion reactions. In view of recent advances, an account focusing on carbene protonation appears to be timely.

II CHEMICAL EVIDENCE FOR CARBENE PROTONATION

The experiments described in this section involve the generation of carbenes in protic solvents, with the aim of detecting carbocations. The section is divided according to the concepts and methods that were applied. First of all, carbenes and carbocations are not readily differentiated as both species feature a vacant p orbital. If that problem has been solved, the origin of the carbocation must be scrutinized. Most often, carbene protonation is not the only possible route to carbocations. Diazo compounds, which are widely used carbene precursors, can give rise to carbocations by way of diazonium ions (Scheme 4).14 The basicity of diazo compounds is known to decrease in the order R,R′ = alkyl > H > aryl > carbonyl > sulfonyl. Diazoalkanes are readily protonated by alcohols whereas some diazo ketones tolerate even carboxylic acids. In order to obtain meaningful results on carbene protonation, the RR′CN2/R″OH mixtures employed must be stable in the dark. This simple criterion is not applicable to labile diazo compounds which are generated in situ from hydrazone precursors. Fortunately, some diazonium ions undergo reactions not shown by the analogous carbocations (e.g., the norbomyl → norpinyl rearrangement).15 The absence of diazonium-derived products is a strong argument supporting the carbene route to carbocations.

Diazirines, which are stable in protic solvents, might be regarded as the precursors of choice for studies on carbene protonation. However, photolyses of diazirines proceed, in part, by way of the isomeric diazo compounds.16 If potent dipolarophiles are present in the reaction mixture, the diazo compounds can be scavenged faster than protonation occurs. Thus the intervention of diazonium ions is avoided, and the carbene route is singled out (for examples, see below). This short survey indicates that nitrogen is a widely applicable but tricky leaving group. Although non-nitrogenous sources of carbenes are available, few of them are compatible with protic media. Some approaches, limited in scope, will be discussed in due course.

A Generation of Delocalized Carbocations

The reaction of carbenes with alcohols can proceed by various pathways, which are most readily distinguished if the divalent carbon is conjugated to a π system (Scheme 5). Both the ylide mechanism (a) and concerted O–H insertion (b) introduce the alkoxy group at the originally divalent site. On the other hand, carbene protonation (c) gives rise to allylic cations, which will accept nucleophiles at C-1 and C-3 to give mixtures of isomeric ethers. In the case of R1 = R2, deuterated alcohols will afford mixtures of isotopomers.

Vinylcarbenes. The use of diazoalkenes as vinylcarbene precursors is often precluded by rapid cyclization, with formation of pyrazoles. However, on photochemical generation of the diazoalkenes in situ, cyclization and nitrogen extrusion can proceed competitively. Photolysis of 1,3-diphenylpropenone to-sylhydrazone sodium salt (5) in MeOD afforded 3,5-diphenylpyrazole (9) and l,3-diphenyl-3-methoxypropene (10) in similar amounts.17 If 10 is formed by way of the 1,3-diphenylallyl cation (8), the deuterium should be distributed between C-l and C-3 of 10 (Scheme 6). The observed ratio of 10a to 10b was 66:34; the methoxy group is bound preferentially to the deuterated site, which originates from the divalent carbon of 7 (for a discussion of this effect, see below).

3,3-Dimethyl-l-phenylpropenylidene (15) was generated from the tosylhydrazone sodium salt 11 as well as from 3,3-dimethyl-5-phenylpyrazole (12), by way of the diazo compound 14.17, 18 The reaction of 15 with methanol gave a mixture of the isomeric ethers 18 and 19, pointing to intervention of the allylic cation 16 (Scheme 7). In order to assess the regioselectivity of 16, the solvolysis of the 4-nitrobenzoate in methanol was also studied. Although 19 prevailed in each case, the 19 : 18 ratio obtained from 11 (1.5) and from 12 (1.7) was inferior to that obtained from 13 (5.1).

The reactions of the vinylcarbenes 7 and 15 with methanol clearly involve delocalized intermediates. However, the product distributions deviate from those of "free" (solvated) allyl cations. Competition of the various reaction paths outlined in Scheme 5 could be invoked to explain the results. On the other hand, the effect of charge derealization in allylic systems may be partially offset by ion pairing. Proton transfer from alcohols to carbenes will give rise to carbocation-alkoxide ion pairs; that is, the counterion will be closer to the carbene-derived carbon than to any other site. Unless the paired ions are rapidly separated by solvent molecules, collapse of the ion pair will mimic a concerted O–H insertion reaction.

The ratio of isomeric ethers is strongly affected by polar substituents which induce an asymmetric distribution of charge in allylic cations. Photolysis of methyl 2-diazo-4-phenyl-3-butenoate (20) in methanol produced 24 in large excess over 25 as the positive charge of 22 resides mainly a to phenyl (Scheme 8).19 As would be expected, proton transfer to the electron-poor carbene 21 proceeds reluctantly; intramolecular addition with formation of the cyclopropene 23 and, eventually, 26 was the major reaction. On the other hand, the carbene 27 should be readily protonated to give the stable benzopyrylium ion 28. In fact, the acetal 29 was obtained as the only product when 27 was generated by photolysis of the analogous tosylhydrazone in MeOH-MeONa (Scheme 9).20 Both carbenes, 21 and 27, add methanol predominantly in a 1,3 fashion: H is bound to the divalent carbon, and OMe to the γ position. The data exclude significant contributions of a non-ionic reaction path.