Recent advances in neutral and anionic N-heterocyclic carbene – betaine interconversions. Synthesis, characterization, and applications

Some mesoionic compounds, i.e. five-membered representatives of the class of conjugated mesomeric betaines (CMB), are in equilibrium with their tautomeric normal N-heterocyclic carbenes (nNHC). In addition, anionic N-heterocyclic carbenes, generated by deprotonation of mesoionic compounds, have been described. The first examples of conversions of cross-conjugated mesomeric betaines (CCMB), 6-oxopyrimidinium-4-olates, into normal N-heterocyclic carbenes have been reported as well. CCMB such as imidazolium-4-carboxylate and pyrazolium-4-carboxylate can decarboxylate to form abnormal (aNHC) or remote N-heterocyclic carbenes (rNHC). Most conversions of betaines into N-heterocyclic carbenes start from pseudo-cross-conjugated mesomeric betaines (PCCMB) which can be regarded as heterocumulene adducts of nNHC. Thus, decarboxylations of imidazolium-2-carboxylates, 1,2,4-triazole-3-carboxylates, pyrazolium-3-carboxylates or indazolium-3-carboxylates yield N-heterocyclic carbenes which have been used in catalysis, complex chemistry


Introduction
3][4] This is surely due to the fact, that mesoionic compounds can only be represented by dipolar canonical forms, which seemed to be counterintuitive, because major contributors to the overall structure of a compound which can be formulated by several resonance structures normally carry a minimum number of charges, if at all.As a consequence, structures, representations and structureactivity relationships had been discussed intensively.

Scheme 1. The first mesoionic compound (1882).
In parallel, mesoionic compounds aroused much interest as biologically active compounds [5][6][7][8] and 1,3-dipoles in [2+3]-cycloadditions. 9,10 In 1955, Katritzky pointed out inconsistencies to be found in the literature and examined critically the value of the descriptive term "mesoionic". 11He suggested that the description "mesoionic" should be discontinued as these compounds are mesomeric betaines and stated that "the introduction of new trivial names and symbols such as ψ to name these compounds is both undesirable and unnecessary". 11esomeric betaines have been defined as compounds which can exclusively be represented by dipolar canonical forms and which delocalize the positive as well as negative charge within a common π-electron system.In 1985 Ollis et al. published a comprehensive classification system which divided all mesomeric betaines into four distinct classes. 12They defined the classes of conjugated mesomeric betaines (CMB), ylides which are closely related to CMBs, crossconjugated (CCMB), and pseudo-cross-conjugated mesomeric betaines (PCCMB).Examples (2 -5) are given in Scheme 2.
Each class forms four subclasses on the basis of isoconjugation to even or odd, alternant or non-alternant hydrocarbon anions and dianions. 12The four major classes of MB can be distinguished by careful inspection of their resonance structures, by dissection of characteristic 1,3-dipoles from their canonical forms, and by their frontier orbital profile. 12Thus, in CMB common sites for positive and negative charges exist in the canonical forms, whereas the charges are restricted to separate parts of the molecule in CCMBs.PCCMBs possess characteristic electron sextet structures without internal octet stabilization, and ylides related to CMBs can best be represented as 1,2-dipoles.Examples are given below (Sections 2.1 -2.4).Reviews dealing with the types of conjugation and their consequences 12,13 and mesomeric betaines as natural products 14 have appeared so that the characteristic differences of these distinct classes should not be repeated here.Since 1985 mesoionic compounds are defined as 5-membered ring systems which belong to the class of conjugated mesomeric betaines (vide infra). 12In 2013, Ramsden predicted the existence of additional classes of mesomeric betaines 15 which await synthesis and characterization.Betaines which delocalize an odd number of charges within a common πelectron system form a distinct class of compounds. 16,17egarding the second-mentioned class of title compounds, it is well known that the isolation of the first stable N-heterocyclic carbene (NHC) 18 by Arduengo led to a remarkable development in synthetic as well as catalytic organic chemistry.1][22] Examples are compounds 6 -8 (Scheme 3).In the first mentioned class the free, non-complexed carbene can be formulated by a neutral electron sextet structure as well as by dipolar structures.Abnormal N-heterocyclic carbenes can exclusively be represented by dipolar canonical forms, therefore the alternative name "mesoionic carbenes" (MIC) has been introduced. 23In remote N-heterocyclic carbenes (rNHC), the carbene carbon must not be adjacent to any heteroatom.Abnormal, mesoionic and remote N-heterocyclic carbene complexes have been reviewed recently, and nomenclature, classification and bonding have also been discussed. 24hrough the eyes of an organic chemist, there is indeed some confusion and inconsistency over the representation of NHC metal complexes.Several resonance forms of NHC metal complexes are plausible (Figure 1, I) and all of them feature tetravalent carbon.The weighted average of these resonance forms, however, strongly depends on the metal.Two of them show a conventional covalent single bond but then the transfer of an electron has to be shown by positive and negative charges.Boron adducts are best represented by these dipolar structures with a positive charge on carbon or nitrogen, which are also entirely consistent with the representation of mesomeric betaines such as mesoionic compounds or heterocumulene adducts of NHCs.Representations of complexes of NHCs with other metals, however, also include resonance forms with C=M double bonds.The link between the C and the metal is in fact a dative bond so that representation II is appropiate, but seems to be unpopular.In representation III the conjugation between the nitrogen atoms is indicated, but no charges.The same is true for representation IV, whereas the saturated carbon in the frequently used representation V implies a CH which is not present, and does not account for the electron distribution.Some authors therefore draw the letter C into the structure as in VI.In order to avoid the formulation of tetrapolar or tripolar structures with two formal negative and one or two formal positive charges within the same molecule, representation III orwhere appropiatea selected dipolar structure taken from the resonance forms I is used throughout this review.

Figure 1. Representations of NHC metal complexes.
Meanwhile interesting relationships between the two classes of compounds, mesomeric betaines and N-heterocyclic carbenes, have been recognized.Reviews covering portions of that field appeared recently (vide infra).Thus, the chemistry of pyrazole-ylidenes and indazolylidenes has been summarized. 25More general review articles deal with syntheses, properties, and biological activities of pyrazoles 26,27 and indazoles, 28 including betaines and carbenes.This interesting area of overlap will serve as strong impetus for additional research in that field.

Interconversions of normal (nNHC) and anionic N-heterocyclic carbenes and conjugated mesomeric betaines (CMB), including mesoionic compounds
According to the aforementioned definition by Ollis, Stanforth and Ramsden, conjugated heterocyclic mesomeric betaines are cyclic mesomeric betaines in which the positive and the negative charges are not restricted to separate parts of the π-electron system of the molecule.The positive and negative charges are in mutual conjugation and both are associated with the common conjugated π-electron system of the molecule. 12Characteristic features of conjugated mesomeric betaines, for which the mesoionic compound sydnone VII is given as an example, are summarized in Figure 2. In the canonical forms, common sites for positive and negative charges exist (VIII).The characteristic dipole type IX can be dissected from the resonance structures.

Figure 2. Characteristic features of conjugated mesomeric betaines (CMB).
Mesoionic compounds are defined as five-membered conjugated mesomeric betaines of the general structures A (mesoionic compounds of type A) or B (mesoionic compounds of type B) (Figure 3).The letters a -f symbolize atoms or groups, and the numbers stand for the π electrons which contribute to the 8 π electron system. 9,10Mesoionic compounds are isoconjugate to the 2methyl-2,4-cyclopentadiene dianion X which is an even-numbered, non-alternant system XI.Mesoionic compounds belong therefore to subclass 4 of the aforementioned categorization. 12228 structures of mesoionic compounds have been theoretically predicted and a large number of those still await synthesis and characterisations. 9,10,12igure 3. Architecture of mesoionic compounds.The 1,2,4-triazolium-3-aminide 9 is a typical mesoionic compound (Scheme 4).It has been used as analytical reagent for the detection of nitrate anions for decades ("Nitron", Busch´s reagent) and was first described more than 100 years ago. 29It was found very recently that nitron is in equilibrium with its N-heterocyclic carbene which undergoes various trapping reactions such as Rh carbonyl complex formation (10, 11), triazolium-dithiocarboxylate formation with CS2 (12), or almost quantitative thione formation with sulfur. 30The reaction leading to 12 is the conversion of the mesoionic compound (9) via its tautomeric N-heterocyclic carbene into a pseudo-cross-conjugated mesomeric betaine (PCCMB) (vide infra).The carbene carbon atom of 10 and 11 appear at δ = 175.9ppm and 184.9 ppm in 13 C NMR spectroscopy, respectively.The bond length of the Rh-Ccarbene bond of 9 was determined by a single crystal X-ray analysis to be 2.077(5) Å, whereas a value of 2.030(4) Å was found in 11.The Tolman electronic parameter of the NHC was calculated to be 2057.4cm -1 , indicative of a moderate donor strength.The ΔG 0 of the betainecarbene interconversion was calculated to be 5.7 kcal/mol in the gas phase.Scheme 4. Tautomeric equilibrium of a mesoionic compound and a normal N-heterocyclic carbene.
The mesoionic compound imidazolium-4-aminide 13 undergoes a similar series of reactions (Scheme 5).The tautomeric carbene of 13a could be trapped as thione with sulfur and as pseudo-cross-conjugated mesomeric betaine (PCCMB) on treatment with CS2, similar to the reactions described above. 31The Rh complex 14 was formed on deprotonation of the precursor of 13a -the corresponding imidazolium salt -with KOtBu in the presence of the in situ prepared dimer [Rh(-OtBu)(COD)]2 at room temperature.The former carbene carbon atom of 14 occurs as a doublet at  = 176.8ppm ( 1 JRhC = 53 Hz).The Rh-Ccarbene bond length was determined by a single crystal X-ray analysis to be 2.053(3) Å. Surprisingly, silica gel and air converted the complex into the Rh complex 15 (X-ray analysis) which was accompanied by a considerable shortening of the Rh-Ccarbene bond to 1.998(3) Å.The complexes 14 and 15 were converted into the dicarbonyl complexes on treatment with CO which were used to determine Tolman´s Electronic Parameter.It was found that the carbene tautomer of 13a has slightly better donor capabilities than 1,3-dimesitylimidazol-2-ylidene.
The mesoionic compound 13b formed an orange-colored, sensitive solid on treatment with base which crystallized on addition of N,N,N´,N´-tetramethylethylenediamine (tmeda) as Li complex 16 possessing an anionic NHC ligand (X-ray analysis). 32The Li-Ccarbene bond has a length of 2.093(3) Å.The green iron complex 17 was prepared by reaction of the Li complex 16 with [{Fe(-Cl)Cl(tmeda)}2] and proved to be extremely air-and moisture sensitive (X-ray analysis).The Fe-Ccarbene bond length was determined to be 2.090(2) Å.The anionic Nheterocyclic carbene 18 was observed spectroscopically.The Ccarbene resonance frequency was found to be at  = 202.3ppm under these conditions.Scheme 5. Mesoionic compounds in equilibrium with normal N-heterocyclic carbenes.
Imidazolium-4-olate 19 is an additional mesoionic compound which has been converted into N-heterocyclic carbenes possessing a negative charge 33 (Scheme 6).Thus, an anionic species was generated with LiHDMS which was then identified by trapping with sulfur. 34,35The free carbene was detected at δ = 209.1 ppm. 35Half an equivalent of the Rhodium dimer [RhCl(COD)]2 followed by acidification converted the anion into the complex 20 which has a keto group (X-ray analysis). 34The Ccarbene atom gives a doublet at  = 229.7 ppm ( 1 JRhC = 51.5 Hz).The complex 20 was deprotonated with LiHMDS in THF at -78°C to the anionic species 21 which was used as a reactive intermediate to functionalize the exocyclic olate group with electrophiles such as diphenylphosphinic chloride [ClPh2P(=O)] and chloro-tertbutyldimethylsilane [TBDMSCl], respectively.On reaction with 1 atm CO in CH2Cl2 at rt, the COD ligand in 20 was replaced to two CO ligands in 96% yield.The complex 19 33 was furthermore converted into the copper complex 22 as reactive intermediate which afforded 23 on treatment with hydrochloric acid and water.The olate group of 22 could successfully be silylated with TBDMSCl.This paper finally presents a comparison of donor properties of 1,3-bismesitylene substituted imidazolylidenes.The 3-olate derivative shows a stretching vibration asym(CO) of 2029.5 cm -1 which proves the character of a very nucleophilic carbene. 34Iridium complexes have also been prepared which possess a phenyl substituent or a butyl group at C-4.They were obtained in the keto form similar to 20. 35 Additional LiHDMS, however, caused a deprotonation to an anionic ligand, the TEP value of which was determined to be 2043.7 cm -1 .This ligand is much more electron rich than IMes or IAd. 35heme 6. Imidazolium-olate / NHC interconversion.
The triazolylidene copper(I) complexes 25a-c reacted with CsOH to give the mesoionic compounds 26a-c (Scheme 7).This method proved to give better yields in comparison to the direct reaction of 24a-c with the same base. 36Complex 25b was isolated in 82% yield.© ARKAT-USA, Inc. Scheme 7. Formation of a mesoionic compound from a NHC copper complex.
5-Azido-1,3-diphenyltetrazolium tetrafluoroborate 27 underwent a spontaneous reaction with sodium azide 37 (Scheme 8).The outcome of the reaction was examined carefully.The filtrate contained phenylazide in high yields, and the precipitate contained the tripolar substance 30, the mesoionic compounds 29 and 32, and the cyanotriazene 31 in various yields depending on the reactions conditions.The authors postulate a heterocyclic carbene as intermediate of this reaction in view of earlier publications [38][39][40] and in view of the fact that the cyanotriazene 31 is the ring-opening product of the carbene.Two mechanisms for the formation of the olate have been discussed, the reaction of carbene with oxygen and the hydrolysis of the starting azidotetrazolium salt.

Scheme 8. Tetrazolylidene and formation of some mesomeric betaines.
Tetrazolylidene was also postulated as intermediate on fluoride-induced dephosphoniation of the dicationic (triphenylphosphonio)tetrazolium salt 34 which was prepared starting from the ylide 33 on 2e -oxidation by nitrosyl tetrafluoroborate 41 (Scheme 9).Cesium fluoride reacted with the dication 34 to the final product tetrazoliumfluoride 38 which is extremely sensitive toward hydrolysis to form the tetrazolium-5-olate 39.This reaction has been interpreted as bromination of the N-heterocyclic carbene 35 to 37 followed by bromine / fluorine exchange.In the absence of bromine, ring-cleavage to the cyanoazimine 36 was observed.The latter mentioned finding hints at formation of an NHC 35 and excludes an alternative mechanism involving the attack of fluoride on the 5-position of the dication 34.The cyanoazimine 36 is also formed on deprotonation of tetrazolium fluoroborate with BuLi at -78 °C.

Scheme 9. Tetrazolylidene generation and conversion into a mesoionic compound.
The oxidation of Emil Fischer´s first mesomeric betaine, the tetrazolium-thiolate 1, with sodium periodate was examined in terms of carbene formation (Scheme 10). 41Tetrazoliumsulfonate 41, the azimine 43, tetrazolium-olate 44, and a dimerized thiolate connected by an S-S bond, were obtained.The betaines 43 and 44 were formed by extrusion of SO2 from tetrazoliumsulfinate 40 via the NHC 42.Scheme 10.Formation of tetrazolylidene from the first mesoionic compound tetrazoliumthiolate.
Another approach to tetrazolylidene was also described (Scheme 11).Thus, the tetrazolium salt 45 was deprotonated quantitatively at -90 °C on addition of BuLi, as evidenced by 1 H-NMR spectroscopy. 13C NMR spectra were obtained at -100 °C which show an unstructured multiplet at 202.4 ppm, belonging to the solvated carbene atom of tetrazolylidene 46.At temperatures above approximately -60 °C, this 5-lithiotetrazolylidene undergoes a ring-cleavage to form the aforementioned cyanoazimines.The carbene was trapped by tosyl azide to form small amounts of the betaine 47 and the tetrazolium azide 48. 42heme 11.Tetrazolylidene formation by deprotonation.
Sydnones such as 49 are the best-known mesoionic compounds (Scheme 12).They can be deprotonated with BuLi or MeMgBr in THF in the cold to form the sydnone anion 50 43,44 which can also be formulated as anionic carbene.This anion was characterized as Li adduct 45 or trapped by various electrophiles such as DMF, N,N-dimethylacetamide or acetaldehyde. 44Alternatively, 4-bromosydnone can exchange its bromine toward Li on treatment with BuLi. 46Another approach to the anionic sydnone 50 is the thermal decarboxylation of lithium sydnonecarboxylate 51 which can be prepared from bromosydnone 52. 45Temperature-dependent vibrational spectrometric examinations of 51 and calculations of the carbene 50 have been carried out. 45heme 12. Sydnone anions.
The sydnone anion reacts with sulfur to give the lithium sydnone-4-thiolate 53 which underwent subsequent reactions with water to 54 and electrophilic species to 55a-c as shown (Scheme 13). 47heme 13.Reactions of the sydnone anion.
Palladium (cis and trans), platinum and mercury complexes 56 -58, prepared starting from 4-bromosydnone, have been described as well (Scheme 14). 48The last-mentioned was employed in the synthesis of 4-alkenylsydnones.More recently, nickel complexes have been described. 49A summary and experimental details are given. 50The palladium complex proved to be active in Suzuki-Miyaura reactions such as the arylation of tetrabromothiophene. 45 Scheme 14. Metal complexes of the sydnone anions.
Sydnonimines 65 can also be deprotonated at C-4 to give anions 66 which can also be formulated as carbenes.These were trapped by Ph2PCl to give 67 (Scheme 16).These bidentate ligands form complexes 68 with palladium. 53Similar complex formation has been reported for sydnones as well. 54,55heme 16.Anions of sydnonimines and trapping reactions.
One equivalent of copper(I) bromide to the lithiated sydnonimine of 75 resulted in the formation of a copper derivative 76 which underwent various cross-coupling reactions catalyzed by a palladium complex (Scheme 18).Thus, 77a-c were synthesized. 56,57heme 18. Cross-coupling reactions starting from sydnonimines.

Interconversions of normal N-heterocyclic carbenes (nNHC) and ylides
According to Ollis, Stanforth and Ramsden, "conjugated heterocyclic N-ylides and related dipolar compounds constitute a subdivision of conjugated heterocyclic mesomeric betaines which can be satisfactorily represented by 1,2-dipolar structures such as N-oxides, in which the negative charge is accommodated at an exocyclic atom or group". 12The imidazolium-indolates XII are new members of this class of compound. 58Characteristically, common atoms for negative and positive charges can be recognized in the resonance structures (XIII, Figure 4).The molecule possesses the characteristic dipole type of conjugated mesomeric betaines (XIV).As XII is isoconjugate with the even non-alternant hydrocarbon dianion XV it is a member of subclass 8 of mesomeric betaines.Deprotonation of the salts 78a-c to the ylides 79a-c was accomplished by a solution of NaOH in EtOH (Scheme 19).As already mentioned, several resonance structures can be drawn, among those a form which possesses either a negative charge or a positive charge at C-2 of the imidazolium ring.The existence of those atoms is characteristic of ylides and conjugated mesomeric betaines.Calculations show that the betaine 79a is ΔG = -9.3kJ/mol more stable than the tautomeric carbene which is not visible in DMSO-d6 solutions by NMR spectroscopy.The carbenes, however, were trapped as thiones in high yields.Reaction of 78 with triethylborane or triphenylborane resulted in the formation of a new heterocyclic ring system 80a-c in good yields (X-ray analysis).This ring system formally is the trapping product of the anionic N-heterocyclic carbene 81 which was examined by means of NMR spectroscopy. 58

Scheme 19. First conversion of ylides into N-heterocyclic carbenes.
To gain insight into the mechanism of this borane adduct formation, some model reactions and NMR examinations have been carried out.Thus, the ylide 78a was treated with triethylborane in MeCN-d3 at rt (Scheme 20).Adduct formation B, not A, was observed, although DFT calculations predicted that the initial coordination of triethylborane to the indolatenitrogen under formation of A is energetically slightly more favored by 19.7 kJ/mol.The formation of the B-Ccarbene-bond was confirmed by a 11 B NMR shift of -12.7 ppm.Moreover, the 15 N NMR resonance frequencies of N1imidazolium (δ = -194.3ppm) and N3imidazolium (δ = -202.8ppm) of B were unambiguously assigned. 58heme 20.Results of spectroscopic examinations: B is observed, not A.

Interconversions of normal, abnormal, and remote N-heterocyclic carbenes (nNHC, aNHC, rNHC) and cross-conjugated heterocyclic mesomeric betaines (CCMB)
Only a small number of reports deal with conversions of cross-conjugated mesomeric betaines (CCMB) into N-heterocyclic carbenes.The 6-oxo-pyrimidinium-4-olate XVI is a typical member of this class of compounds (Figure 6).In the canonical forms, the charges are strictly separated in different parts of the common π-electron system (XVII).The characteristic dipole type of cross-conjugated mesomeric betaines can be dissected from the resonance structures (XVIII).The anionic part of the molecule is joined by union bonds ("u") 60,61 through unstarred positions of the isoconjugate hydrocarbon equivalent to the cationic part (XIX).These positions are nodal positions of the highest occupied molecular orbital (HOMO) of this building block of the CCMB (XX).The betaine XVI is isoconjugate with the even alternant hydrocarbon dianion XXI and belongs therefore to subclass 11 of heterocyclic mesomeric betaines.The 6-oxopyrimidinium-4-olate 85 was transformed into the lithium salt of a stable anionic N-heterocyclic carbene 86a 62,63 (Scheme 22).In the single crystal, a trimeric annular association can be seen, where three Li(thf) 2+ units serve as linkers between the 6-oxopyrimidinium-4-olate molecules which bind through their oxygen atoms to the lithium.The rhodium complexes 87a,b (X-ray analysis) were formed as neutral 14 electron complexes starting from the anionic carbene either generated with nBuLi or with KHMDS.The silver complex 88 was produced on reaction of mesomeric betaine 85b with KHDMS followed by the addition of Ph3PAgOTf; the iron complex 89 was described as well (X-ray analysis).The bond distances have been determined to be Ccarbene-Rh = 2.036(1) Å, Ccarbene-Ag = 2.122(1) Å, and Ccarbene-Fe = 2.041(1) Å.

Scheme 22. Conversion of a cross-conjugated mesomeric betaine into a N-heterocyclic carbene.
Pyrazolium-4-carboxylates XXII and imidazolium-4-carboxylates XXVII represent another architecture of cross-conjugated mesomeric betaines (Figure 7).They also fulfill all characteristic features of this class of compounds, such as charge distribution in strictly separated parts of the molecule according to the canonical forms (XXIII, XXVIII), bond through unstarred positions (XXV, XXX) or nodal positions of the HOMO of the anionic part (XXVI, XXXI) to the cationic part of the betaine.Characteristic dipole types can be dissected from the resonance forms (XXIV, XXIX).They are isoconjugate with even non-alternant hydrocarbon dianions which is subclass 12 of mesomeric betaines. 12As pointed out earlier, these types of crossconjugated mesomeric betaines are formal 1 : 1 adducts of heterocumulenes such as CO2 of the remote NHC (rNHC) pyrazol-4-ylidene and the abnormal NHC (aNHC) imidazol-4-ylidene, respectively.The highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) are consequently located in separated parts of the common π-electron system. 64The generation of carbenes from these types of mesomeric betaines is seemingly limited due to harsh reaction conditions which are in sharp contrast to the relatively mild conditions which have to be applied to analogous reactions of pseudo-cross-conjugated molecules.A detailed discussion is given in Chapter 2.4 (vide infra).A thermal N-demethylation / Omethylation sequence was observed on heating of pyrazolium-4-carboxylate 90 in mesitylene at reflux temperature to yield the pyrazole ester 91 (Scheme 23).The decarboxylation to pyrazole-4-ylidene 92 was observed mass spectrometrically, and the carbene was detected as sodium or lithium adduct.Calculations predict a much higher energy barrier (120 kJmol -1 ) for the decarboxylation of 90 in comparison to its pseudo-cross-conjugated isomer (vide infra). 64heme 23.A remote N-heterocyclic carbene from a cross-conjugated mesomeric betaine.
The cross-conjugated mesomeric betaine 93 occurs in nature and is known as alkaloid norzooanemine (Scheme 24). 14In order to study thermal decarboxylations to an abnormal Nheterocyclic carbene, its 2-deuterio-derivative 93-d1 was prepared and subjected to mass spectrometric examinations.It was found that at higher fragmentor voltages than approximately 30 V the decarboxylation to 2-deuterioimidazol-4-ylidene [93-d1-CO2] takes place under the conditions of electrospray ionization mass spectrometry.The corresponding monodeuterioimidazolium salt (93-d1-CO2+H + ) and traces of the normal N-heterocyclic carbene (93-d1-CO2+H + -D + ) were also detected.No deuterium exchange reactions during the electrospray ionization process were identified. 65heme 24.Results of spectroscopic examinations on carbene formation.

Interconversions of normal N-heterocyclic carbenes (nNHC) and pseudo-crossconjugated mesomeric betaines (PCCMB)
[15]60,61 The differences become apparent when interconversions to N-heterocyclic carbenes and related species are compared.Pseudo-cross-conjugated mesomeric betaines can best be recognized by canonical forms which are electron sextet structures without internal octet stabilization.Imidazolium-2-carboxylate XXXII is given as an example (Figure 8).Characteristic dipole types can be dissected from the resonance structures (XXXIII). 12Similar to cross-conjugated mesomeric betaines, the anionic part of the betaine is joined by union bonds ("u") to the cationic part via unstarred positions of the isoconjugated hydrocarbon equivalent (XXXIV), and these are nodal positions of the HOMO of the anionic building block (XXXV). 60,61Pseudo-crossconjugated mesomeric betaines of type XXXII are isoconjugate with even non-alternant hydrocarbon dianions which form class 16 of heterocyclic mesomeric betaines. 12They are (more than) formal 1:1 adducts of heterocumulenes with normal N-heterocyclic carbenes (nNHCs).Indeed, type XXXII betaines are air-stable and can be used without any particular precautions as NHC precursors (vide infra).The area of overlap between the classes of pseudo-cross-conjugated mesomeric betaines and normal N-heterocyclic carbenes (nNHC) is by far the most important because of interconversions under relatively mild conditions.Some reviews covering portions of that field appeared during the last years.A detailed review on betaine adducts of N-heterocyclic carbenes was published in 2009. 66This review cites 102 references and deals with carbon disulfide, carbon dioxide, isothiocyanate, isocyanate, carbon diselenide, carbodiimide, and prop-1-ene-1,1,3,3-tetracarboxylate adducts of N-heterocyclic carbenes 96 -107 (Scheme 26).All adducts belong to the class of PCCMB.
The outstanding feature of pseudo-cross-conjugated mesomeric betaines is the formation of normal N-heterocyclic carbenes by cleavage of the union bond which connects the positive and the negative part of the molecule, and especially decarboxylations proved to be advantageous as they often proceed under relatively mild conditions, when stabilizing effects such as hydrogen bonds are absent.As a matter of fact decarboxylations of thiazolium, oxazolium and imidazolium carboxylates were studied almost 50 years ago, 73 and these results offer an interesting comparison between pseudo-cross-conjugated and cross-conjugated systems.It was shown that the 2-and 5-carboxylic acids of the aforementioned heteroaromatics 108 and 109 decarboxylate through zwitterionic tautomers (Scheme 27).In the case of imidazole-2-carboxylic acids, these are indeed the predominant tautomers. 74Similar results have been obtained for the decarboxylation of oxazole-2-carboxylic acid. 75The fastes rate of decarboxylation of the thiazole-2-carboxylic acid was observed in the neutral solvent ethylene glycol.Decarboxylations of the N-methylated species, i.e. the mesomeric betaines 110 have been examined as comparison.
As a matter of fact, the thiazolium-2-carboxylate 111 is quite unstable as it decarboxylates easily at rt after a few minutes.It was used to induce benzoin condensations in the absence of base (Scheme 28). 76

Scheme 29. Reaction of water with imidazolium-2-carboxylates in CD2Cl2.
Replacing alkyl substituents attached to nitrogen to the bulky tBu group, the C=O stretching decreases. 77N-Aryl substituents cause higher νCO(asym.)stretching frequencies (Scheme 30). 77Thermal stabilities have been examined by means of FTIR spectroscopy with monitoring the (CO2) region. 78Interestingly, the presence of free CO2 significantly stabilizes the betaines toward decarboxylation, while the addition of propylene oxide causes a destabilization of the betaines.Organocatalytic properties have been investigated. 78cheme 30.Stretching frequencies of the νCO(asym.)band of PCCMBs are affected by the steric bulk of the substituents attached to the nitrogen atoms.
Increasing ability to decarboxylate was found by TGA analyses with increasing steric bulk of the substituents attached to the N atoms. 77Thus, 1,3-dimethylimidazolium-2-carboxylate 113 decarboxylates at 162 °C, whereas the corresponding tBu derivative 117 loses CO2 at 71 °C and decomposes.These temperatures were dependent on the amount of sample and were found for 3.5 mg.It was found also that extra electron density in the imidazolium ring by substitution of methyl groups in the position 4 and 5 enhances the stability of the betaines 77 and causes an increased basicity of the resulting carbene. 79A direct correlation was found between the bond lengths of the union bond connecting the positive and negative fragments of the betaines and the decarboxylation temperature. 77Smaller bond lengths cause higher decarboxylation temperatures.Torsional angles around this union bond were identified as additional parameters, as this becomes larger the decarboxylation temperature decreases.This shows impressively the close, but subtle difference between the classes of conjugated, cross-conjugated and pseudo-crossconjugated mesomeric betaines.Interestingly, some results of single crystal X-ray analysis indicate that the cleavage of the union bond may also be mechanical in nature. 77he mild decarboxylation conditions of PCCMB were used in interesting betainecarbene salt interconversions.Thus imidazolium and benzimidazolium hydrogen carbonates versus imidazolium-2-carboxylates have been studied as organic precatalysts for N-heterocyclic carbene catalyzed reactions (Scheme 31). 80,81Thermogravimetric analyses coupled with mass spectrometry of most of the examined hetarenium hydrogen carbonates displayed an extrusion of water and carbon dioxide in stages.

Scheme 31. Carbon dioxide trapping and extrusion.
Depending on the substitution pattern, either a concomitant or stepwise release of water and CO2 was observed between 108 °C and 280 °C.In solution, decarboxylation occurred at rt. Cyanosilylations, benzoin condensations, and transesterifications were studied, where the carbene-carboxylates proved to be three times more efficient than the hydrogen carbonate counterparts.
Decarboxylations of pseudo-cross-conjugated azolium-carboxylates have been employed in a large number of syntheses.Thus, a phosphane / NHC ligand exchange was performed starting from the PCCMB imidazolium-2-carboxylate in refluxing THF (Scheme 32).The new second generation ruthenium(II) dichloride-indenylidene complex proved to be stable in the solid state and was tested in catalytic reactions.The Ru-Ccarbene bond length is 2.091(5) Å. 82 The corresponding PCy3 complex was prepared similarly. 83heme 32.Formation of Ru complexes starting from a PCCMB.
The borane adduct 127 was also formed on thermal decarboxylation of PCCMB 113, 89 which has also been used as ionic liquid precursor. 90Trapping of the carbene was accomplished with PhPCl2 to form 128 (Scheme 34). 91heme 34.Trapping reactions with boron and phosphorus electrophiles.
In a reversed process, numerous frustrated Lewis pairs (FLPs) such as 129 were used for CO2 fixation as 130 (Scheme 35). 92

Scheme 35. CO2 trapping reactions.
A bis-N-heterocyclic carbene 131 connected by a redox active p-quinone moiety was prepared which gave the bis-betaine 132 on treatment with ferrocenyl isothiocyanate (FcNCS) 93 (Scheme 36).This was then converted into bimetallic complexes as part of a study directed to electron-configurable compounds.The union bond connecting positive and negative part of the molecule was determined to have a bond length of 1.486(7) Å by X-ray crystallography.The dihedral angle between these two molecule fragments is 88.7 (6).
The chemistry of N-heterocyclic carbenes and mesomeric betaines of pyrazole and indazole has been reviewed recently, 25 and reviews dealing with syntheses, properties, and biological activities of pyrazoles 26,27 and indazoles 28 appeared as well.Therefore, only a brief overview will be given here.Pyrazole-3-ylidene 137 was first generated by thermal decarboxylation of the pseudo-cross-conjugated heterocyclic mesomeric betaine 136 and was examined by electrospray ionization mass spectrometry (Scheme 38). 102,103The in situ generated NHC proved to induce aldol additions, Knoevenagel reactions, and redox esterifications. 102heme 38.Pyrazol-3-ylidene from the PCCMB pyrazolium-3-carboxylate.
Raman spectroscopy was found to discriminate between cross-conjugation of pseudocross-conjugation of pyrazolium-carboxylates, as key bands react sensitive toward conjugation effects. 1042,5-Dimethyl-1-phenylpyrazolium-3-carboxylate and its crossconjugated isomer 1,3-dimethyl-2-phenylpyrazolium-4-carboxylate were measured and the results were compared with theoretical values (DFT-B3PW91) calculated at the 6-311+G(d,p) level.The asymmetric stretching vibration of the carboxylate group at 1636 cm -1 of the PCCMB is shifted to 1589 cm -1 in the CCMB, resolved by Fourier deconvolution from a shoulder of an intense band at 1598 cm -1 (Figure 9).A similar difference, although with opposite tendency, was found for the symmetric stretching vibration.Raman wavenumbers are known to strongly sensitive to the carboxylate negative charge density.In CCMB 138, the negative charge is exclusively located on the carboxylate group, and both CO stretching modes are equivalent.The spectra resolve their antisymmetric and symmetric stretching modes.In the PCCMB 136 a slight interaction across the union bond causes a more single-bond stretching mode (1333 cm -1 ) and a more double-bond stretching mode (1636 cm -1 ).
It was found that the chemical behavior of pyrazolium-3-carboxylates strongly depends on their substitution pattern.Systems possessing an aromatic ring in position 1 such as 139a-d undergo decarboxylation on heating to N-heterocyclic carbenes which spontaneously rearrange in a pericyclic reaction to 4-aminoquinolines 141a-d, 105 insofar as at least one unsubstituted ortho position exists (Scheme 39).The mechanism has been calculated. 106Likewise, indazol-3ylidenes rearrange to functionalized acridines. 107heme 39.Pericyclic rearrangements of pyrazole-3-ylidenes generated from PCCMB.
Quantum mechanical studies and vibrational spectra of indazolium-3-carboxylates 145 and the N-heterocyclic carbene indazol-3-ylidene 146 generated by decarboxylation have been reported 108 (Scheme 41).Normal mode analyses were applied to analyze changes in the stretching force constants (SFC) on decarboxylation to establish spectroscopic-structure relationships.The two stretching modes were assigned to two relatively intense infrared bands at 1657 cm -1 and 1320 cm -1 .The corresponding Raman bands are given in Scheme 41.According to this, betaine 145 possesses a union bond with a bond length of 1.559 Å, the stretching force constant of which was measured be 2.83 mdynÅ -1 , which is a very low value.A single crystal Xray analysis showed a bond length of 1.519 Å of the union bond in the solid state which is considerable longer than a C(sp 2 )-C(sp 2 ) single bond (147 pm).In the elemental cell, the carboxylate group adopts a torsional angle of 21.5° with respect to the indazole ring. 109The weakest skeletal SFC of the molecule was calculated for the N-N bond.Quantum mechanical modeling gave values for N-heterocyclic carbene 146 which are shown in Scheme 41. 108 Greater changes are found for the SFC of the N-N bond which change by 31.2% on conversion of the betaine to the carbene.Low activation energies of 11.35, 11.76, and 12.33 kcal mol -1 were calculated for the decarboxylation of 145 and its 5-fluoro and 5-chloro derivative from the solid state, respectively, which correlates well with the starting decarboxylation temperatures determined experimentally by thermogravimetric analyses, 116 °C, 100 °C, and 94 °C. 109The decarboxylation could also be monitored by infrared and Raman spectroscopy at varying temperatures as the CO2 molecules were detectable as a band at 2335 cm -1 . 108Scheme 41. Results of quantum chemical calculations [DFT, 6-311+G(d,p)].
The pseudo-cross-conjugated mesomeric betaine 145 is stabilized by hydrogen bonds from water or polar protic solvents.Thus, the X-ray single crystal analysis showed three equivalent of water of crystallization. 109Destabilization consequently occurs in non-polar solvents which form azeotropic mixtures with water.Under these conditions, decarboxylation begins at ambient temperatures, which is concomitant to a considerable decrease of the permament dipole moment from 11.85 D (145) to 4.50 D (146). 108Thus a solution of 145 in DMSO-d6 contained 35% of corresponding indazolium salt, formed by a decarboxylation / protonation sequence, after 10.0 minutes at 25 °C.NMR measurements at various temperatures show a considerable decarboxylation above approximately 40 °C. 110The Gibbs free energy difference for the decarboxylation of the betaine 145 at 25 °C at 1 atm was calculated to be 3.4 kcal/mol. 84A threshold temperature of 38 °C was theoretically predicted, necessary for the decarboxylation of 145 to start under a pressure of 1 atm.The singlet ground state of the N-heterocyclic carbene 146 was calculated to be 45.2 kcal mol -1 more stable than the triplet ground state, which have been compared. 110he in situ generated indazol-3-ylidene 146 undergoes typical trapping reactions in solution as shown under formation of new pseudo-cross-conjugated mesomeric betaines such as 148 and 149 (Scheme 42). 109heme 42.Indazol-3-ylidene generated from the PCCMB indazole-3-carboxylate.
N-Methylpyridinium-3-carboxylates such as 158 and N-methylpyridinium-2-carboxylates 159 represent two additional examples of CCMB and PCCMB, respectively, which have been compared in terms of their abilities to generate N-heterocyclic carbenes (Scheme 44).The former mentioned CCMB is known as the alkaloid trigonelline and the latter as alkaloid homarine. 14The PCCMB 159 has been used in heterocyclic synthesis due to the ease of its decarboxylation (vide infra).Scheme 44.Two natural products belong to the classes of CCMB (158) and PCCMB (159).
Nine isomeric pyridinium dicarboxylates, among those the N-methylpyridinium-2,3dicarboxylate 160, were examined by negative ion photoelectron spectroscopy as model substances to gain knowledge about the mechanisms of orotidine 5´-monophosphate decarboxylase (Scheme It was found that the expulsion of CO2 is facilitated from the pseudo-cross-conjugated position.The authors claim that this might seem to be counterintuitive as the remote carboxylate is less affected by the positive charge, but they say that any reasonable application of Coulomb´s law indicates that more is gained by expulsion of the 2-carboxylate because of the greater stabilization of the resulting carbanion.The relative stabilities of the resulting decarboxylated species are largely determined by their intramolecular electrostatic interactions.The zwitterion 161 derived from 3-decarboxylation has a relative stability of 22.7 / 130.7 kcal mol -1 according to B3LYP/3-31+G(d) and Coulomb´s law calculations, whereas the 2decarboxylated species 162 has values of 15.7 / 62.4 kcal mol -1 , respectively, so that the latter mentioned is more stable than the former.Ylide formation to 163 is exothermic by -16.9 kcal mol -1 .

Interconversions of normal, abnormal, and remote N-heterocyclic carbenes (nNHC, aNHC, rNHC) and zwitterions
The term "zwitterion" is not well defined.It sometimes describes molecules with an interrupted conjugation between the charged parts of the molecule, for example by one or more sp 3 hybridized carbon atoms, as with the aminoacids. 14Some polyheterocyclic molecules, however, can form zwitterionic ground states, in which both the negative and the positive charge are delocalized within a common π-electron system, although at least one uncharged covalent structure can be drawn. 122Those molecules are best represented by dipolar resonance structures which are also called zwitterions despite of the fundamental structural differences to the aforementioned class of compounds.Borane adducts of N-heterocyclic carbenes do not fit into the classification system of conjugated mesomeric betaines (CMB), because according to the valence bond theory the charge which is located on the boron atom is not part of the π-electron system.On the other hand, no characteristic features of conjugated, cross-conjugated, and pseudo-cross-conjugated mesomeric betaines can be recognized in these borane adducts.Nevertheless, they do share a formal relationship to this class of compounds.Thus, formal replacement of the olate group in imidazolium-4-olate to a borate group results in borane adduct 172 (Scheme 47).Formal replacement of the carboxylate group in imidazolium-2-and 4carboxylates gives borane adducts 171 and 172.Borane adduct formations from N-heterocyclic carbenes have been reviewed recently. 123Here, examples of the title compounds will be presented.A comprehensive survey about the interesting subject of NHC adduct formation with trivalent group 13 compounds, [124][125][126][127][128] however, is beyond the scope of this review.The frustrated carbene-borane Lewis pair 170a·B(C6F5)3 formed the aNHC-borane adduct 172 129 which is more stable than the corresponding nNHC-borane adduct. 130The sterically less demanding Dipp (2,6-diisopropylphenyl) substituent in 170b resulted in the formation of the "normal" borane-NHC adduct 171. 131Either compound failed deprotonation to give an anionic N-heterocyclic borane.These were prepared by deprotonation to form 173 followed by treatment with the borane to give 174. 132heme 47. Borane adduct formations to normal and abnormal N-heterocyclic carbenes.
An anionic N-heterocyclic dicarbene 176 has been prepared as a polymeric chain (X-ray structure) in excellent yield on treatment of the nNHC 175 with nBuLi in hexane at rt and subsequent addition of THF / TMEDA (tetramethylethylenediamine), or by addition of lithium in THF.The THF adduct proved to be persistent at rt under an inert atmosphere (Scheme 48). 133riethylborane and trimethylaluminum reacted to the adducts 178 and 177, respectively.The borane adduct has been converted into the zwitterions 179. 134heme 48.Formation of a dicarbene.

Conclusions
The chemistry of heterocyclic mesomeric betaines and of N-heterocyclic carbenes have an interesting area of overlap.Depending on the type of conjugation (pseudo-cross-conjugation, cross-conjugation, conjugation) and the architecture of the mesomeric betaine, the distinct classes of N-heterocyclic carbenes (normal, abnormal, remote) are available.Table 1 summarizes the mesomeric betaine ↔ N-heterocyclic carbene transformations described in this review.N-Heterocyclic carbene formations from mesomeric betaines have been performed so far by tautomerism of type-A mesoionic compounds which are members of the class of conjugated mesomeric betaines (1), by tautomerism of ylides (2), by extrusion of heterocumulenes as leaving groups from iminium-2-heterocumulene adducts i.e. from pseudo-cross-conjugated mesomeric betaines (3), or from X=Y=Z adducts in position 2 of prop-2-en-1-iminium partial structures (4) which belong to cross-conjugated mesomeric betaines (X=Y=Z: CO2, SO2) (Figure 10).

Figure 10 .
Figure 10.General scheme of the formation of NHC from mesomeric betaines

Table 1 .
Mesomeric betaine ↔ N-heterocyclic carbene transformations described in this review