Formation and Stability of N-Heterocyclic Carbenes in Water:  The Carbon Acid pK_aof Imidazolium Cations in Aqueous Solution

Abstract

We report second-order rate constants kDO (M-1 s-1) for exchange for deuterium of the C(2)-proton of a series of simple imidazolium cations to give the corresponding singlet imidazol-2-yl carbenes in D2O at 25 degrees C and I = 1.0 (KCl). Evidence is presented that the reverse protonation of imidazol-2-yl carbenes by solvent water is limited by solvent reorganization and occurs with a rate constant of kHOH = kreorg = 10(11) s-1. The data were used to calculate reliable carbon acid pK(a)s for ionization of imidazolium cations at C(2) to give the corresponding singlet imidazol-2-yl carbenes in water: pKa = 23.8 for the imidazolium cation, pKa = 23.0 for the 1,3-dimethylimidazolium cation, pKa = 21.6 for the 1,3-dimethylbenzimidazolium cation, and pKa = 21.2 for the 1,3-bis-((S)-1-phenylethyl)benzimidazolium cation. The data also provide the thermodynamic driving force for a 1,2-hydrogen shift at a singlet carbene: K12 = 5 x 10(16) for rearrangement of the parent imidazol-2-yl carbene to give neutral imidazole in water at 298 K, which corresponds to a favorable Gibbs free energy change of 23 kcal/mol. We present a simple rationale for the observed substituent effects on the thermodynamic stability of N-heterocyclic carbenes relative to a variety of neutral and cationic derivatives that emphasizes the importance of the choice of reference reaction when assessing the stability of N-heterocyclic carbenes.

Proton Transfer Reactions of Triazol-3-ylidenes: Kinetic Acidities and Carbon Acid pKa Values for Twenty Triazolium Salts in Aqueous Solution

“…Evidence was presented in earlier work by Amyes et al 22 and us 24 The k DO values in Table 1 Although the k p /k reorg ratios clearly illustrate that re-protonation of thiazolylidenes and solvent reorganization occur at similar rates, Washabaugh and Jencks state that the extent of internal return should be interpreted conservatively because the errors are ± 30% or more. 29 For the determination of a pK a value for N-cyanomethylthiazolium salt 24…”

“…The kinetic acidities towards deprotonation of all triazolium ions by deuteroxide ion via Pathway A (k DO , Table 1) are significantly higher than for analogous imidazolium, 22,24 4,5-dihydroimidazolium 24 and thiazolium ions 27 The triazolium salts in Table 1 are also substantially more acidic than any thiazolium salt studied to date under similar reaction conditions, although the latter experiments have been limited to N-alkyl substituted examples. 27 We have measured a suggested that the more electron withdrawing N-pentafluorophenyl triazolium salts are more acidic than the corresponding N-mesityl salts.…”

“…Buffer catalysis of exchange was also not significant in previous studies of the analogous deuterium exchange reactions of imidazolium, dihydroimidazolium and trihydropyrimidinium ion precursors to carbenes 2-4. 22,24 For the triazolium salts 8a-f-BF 4 -, 9-Cl -, 13-BF 4 -, 14c-f Cl -and 16-BF 4 -studied in fully aqueous solution, values of k ex increase with pD in the region from pD = 0 to 4.5. Figure 2 shows the fit of the log k ex -pD data to eq 3, which is derived from eq 4, where k DO (M -1 s -1 ) is the second-order rate constant for deuteroxide-catalyzed exchange, K W = 10 -14.87 46 is the ion product of D 2 O at 25 o C and γ DO is the activity coefficient for deuteroxide ion under our experimental conditions.…”

“…It is common in many synthetic transformations to generate the active NHC species in situ from the conjugate acid azolium ion precursor of the NHC by use of an appropriate base. 20 Remarkably, despite the widespread use of azolium ion precursors to NHCs in organocatalysis and elsewhere, there have been relatively few literature reports of the solution kinetic or thermodynamic Brønsted acidities of these precatalysts, [21][22][23][24][25][26][27][28][29][30][31][32] although there have been studies of NHC nucleophilicities 33 and gas phase proton affinities. [34][35][36][37][38][39][40][41][42] Washabaugh and Jencks reported on the C2-H/D exchange and aqueous pK a values of a range of N-alkyl thiazolium ion analogues of thiamine, that are precursors to thiazol-2-ylidenes 1.…”

“…[27][28][29] Amyes et al reported aqueous pK a values for the conjugate acids of N,N-dialkylimidazol-2-ylidenes 2 (R = R' = H or Me) and two benzoannelated variants. 22 We recently reported the kinetic acidities towards hydroxide ion, and the aqueous pK a values, of a broad range of conjugate acid precursors to imidazol-2-ylidenes 2, imidazolin-2-ylidenes 3 and trihydropyrimidin -2-ylidenes 4. 24 In this paper, we report kinetic acidities and pK a values in aqueous solution for a large series of synthetically relevant triazolium ion precursors to triazol-3-ylidenes 5.…”