Rate and equilibrium constants for the addition of triazolium salt derived N-heterocyclic carbenes to heteroaromatic aldehydes

Heteroaromatic aldehydes are often used preferentially or exclusively in a range of NHC-catalysed processes that proceed through the generation of a reactive diaminoenol or Breslow Intermediate (BI), with the reason for their unique reactivity currently underexplored. This manuscript reports measurement of rate and equilibrium constants for the reaction between N-aryl triazolium NHCs and heteroaromatic aldehydes, providing insight into the effect of the NHC and heteroaromatic aldehyde structure up to formation of the BI. Variation in NHC catalyst and heteroaromatic aldehyde structure markedly affect the observed kinetic parameters of adduct formation, decay to starting materials and onward reaction to BI. In particular, large effects are observed with both 3-halogen (Br, F) and 3-methyl substituted pyridine-2-carboxaldehyde derivatives which substantially favour formation of the tetrahedral intermediate relative to benzaldehyde derivatives. Key observations indicate that increased steric hindrance leads to a reduction in both k2 and k−1 for large (2,6-disubstituted)-N-Ar groups within the triazolium scaffold, and sterically demanding aldehyde substituents in the 3-position, but not in the 6-position of the pyridine-2-carboxaldehyde derivatives. As part of this study, the isolation and characterisation of twenty tetrahedral adducts formed upon addition of N-aryl triazolium derived NHCs into heteroaromatic aldehydes are described. These adducts are key intermediates in NHC-catalysed umpolung addition of heteroaromatic aldehydes and are BI precursors.


Introduction
The umpolung activation of aldehydes using N-heterocyclic carbene (NHC) catalysts is a widely applicable reaction mode and is generally regarded as a cornerstone of organocatalysis. These reactions harness the ability of NHCs to generate a key catalytic intermediate diaminoenol, commonly referred to as the Breslow Intermediate (BI, Scheme 1), in a remarkable range of synthetic processes. 1 In recent reports, a signicant trend has emerged in the preferred or sometimes exclusive use of heteroaromatic aldehydes as substrates, with furyl-, pyridyl-and quinolyl-derivatives commonplace despite reasons for their preferential reactivity remaining relatively unexplored. 2 As well as providing unique reactivity, the incorporation of these heteroaromatic motifs in NHC-catalysed reactions is of widespread interest due to their importance in target bioactive compounds and natural products. 3 As representative examples, interception of the BI (derived from heteroaromatic aldehydes and the NHC catalyst and acting as an acyl anion equivalent) with alternative electrophiles has been harnessed in NHC-catalysed transformations (Scheme 1). In a rare example of cross-benzoin reactions with heteroaromatic aldehydes, Gravel demonstrated the diastereoselective benzoin reaction of heteroaromatic aldehydes (predominantly using furfural) with enantiopure alkyl amino aldehydes (Scheme 1a). 4 In related reports, the observed anti-diastereoselectivity was rationalised to be dependent upon the N-H substituent, with use of tertiary amines leading to syn-diastereoselectivity. 5 In 2013 Gaunt reported the formation of ketones from a range of heteroaromatic aldehydes via arylation of the corresponding Breslow intermediate using iodonium salts to give a wide range of heteroaromatic ketones in good to excellent yields (Scheme 1b). 6 Furthermore, in 2009, Rovis demonstrated the enantioselective intermolecular Stetter-type addition of heteroaromatic aldehydes (predominantly 2-pyridine carboxaldehyde) to nitro-olens giving the addition products in excellent yield and er (Scheme 1c). 7a Based upon invariance in reactivity and selectivity with electronic variation within the heteroarene, it was suggested that the pyridine nitrogen lone pair was not acting as a base in this transformation but may bias reactivity due to steric effects when compared with benzaldehydes. 7b Despite signicant interest in the use of NHCs as organocatalysts, complete and rigorous mechanistic studies of processes proposed to involve the BI are still limited, with signicant discussion of the role and character of the BI still ongoing. 8 The original mechanism proposed by Breslow in 1958 (ref. 9) was based on Lapworth's mechanism for cyanidecatalysed benzoin formation 10 and proceeds through a tetrahedral adduct of the NHC and aldehyde followed by proton transfer to form the reactive aminoenol (Scheme 2a). Reaction with aldehyde and elimination of the catalyst gives the homobenzoin product. In recent studies, evidence of radical intermediates in the benzoin reaction has been shown computationally and experimentally, particularly in the presence of molecular oxidants, indicating that radical intermediates are feasible and should be considered. 11 Under the polar protic conditions explored in this manuscript, an ionic protontransfer mechanism is expected to dominate due to the rapidity of proton exchange under the methanolic reaction conditions. Furthermore, no radical derived side products have been observed under our reaction conditions.
In previous work, our groups investigated the rate and equilibrium constants for the reaction of NHCs derived from triazolium salts with benzaldehydes in triethylamine buffered methanol (CD 3 OD and 0.18 M Et 3 N : Et 3 N$HCl (2 : 1) buffer at 25°C ). 12 Benzaldehydes bearing heteroatomic 2-substituents exhibited signicantly higher K exp than the parent benzaldehyde (Scheme 2b). For example, 2-methoxybenzaldehyde (R = OMe) gave a ten-fold increase in K exp when compared with benzaldehyde. Further kinetic investigation of the reaction of various aldehydes with triazolium salts revealed that the increase in K exp for 2-substituted aldehydes was a compound result of an increase in k 1 and a reduction in k −1 for formation and decay of tetrahedral hydroxyaryl adduct, respectively. Despite the high K exp , 2-substituted aldehydes do not react selectively as nucleophilic partners in cross benzoin reactions. Instead, they are highly selective electrophilic partners, with this selectivity ascribed to onwards reactivity post BI formation. Also identied in this study, was an increased K exp for 2-pyridyl carboxaldehyde in CH 2 Cl 2 in comparison with benzaldehyde.
Intrigued by these observations, and the use of heteroaromatic aldehydes in NHC organocatalysis, we sought to investigate the kinetics of the reaction of heteroaromatic aldehydes with NHCs to determine if trends in reactivity could be identied. In this manuscript, the synthesis and isolation of a large range of tetrahedral adducts (20) formed from NHCs derived from triazolium salts and heteroaromatic aldehydes are reported (Scheme 2c). 13 Kinetic analysis of tetrahedral adduct formation and decay was performed, and the effect of both catalyst structure (N-aryl substitution, variation of the fused ring-size (n) and incorporation of an oxygen atom within the fused ring) as well as heteroaromatic aldehyde structure on these rates is reported. Given the enormous interest in incorporating heteroaromatic groups into pharmaceutical and agrochemical compounds, understanding the reactivity of these heteroaromatic aldehydes in NHC-catalysed processes will be of signicant interest.

Synthesis and characterisation of tetrahedral adducts
To compare the rate and equilibrium constants for NHC addition to heteroaromatic aldehydes, characterisation of the corresponding tetrahedral adducts to allow unambiguous conrmation of their constitution was required (Scheme 3). Studies therefore began with the isolation of tetrahedral adducts through stoichiometric reaction of the NHCs derived from triazolium salts and heteroaromatic aldehydes in CH 2 Cl 2 at room temperature. The reactions were allowed to reach equilibrium before direct purication by ash column chromatography to give the tetrahedral adducts in acceptable to good yields. A notable exception to this generalisation was observed when triazolium salts with 6-and 7-membered (n = 2, 3) auxiliary rings were used, with isolated yields generally lower, ranging from 27% to 45%. A selection of heteroaromatic aldehydes and triazolium salts were employed to facilitate the investigation of various steric and electronic aspects of each reaction component. For the heteroaromatic aldehydes, pyridine-2-carboxaldehyde derivatives with substituents in the 3-position (ortho to the aldehyde, R) or 6-position (ortho to the pyridine nitrogen, R ′ ) as well as furfural were employed. For the triazolium salts, structural changes included variation of the N-aryl substituent on the triazolium nitrogen (Ar), variation of fused ring-size (n) and incorporation of an oxygen atom within the fused ring (X). Unfortunately, tetrahedral intermediates arising from the use of N-C 6 F 5 substituted azolium salt 1 were not stable to purication and could not be isolated, although N-Ph, N-Mes and N-C 6 Cl 3 H 2 substituted variants proved isolable. 14 X-ray crystallographic analysis of 13 allowed unambiguous conrmation of product constitution. 15 Due to their propensity to onward reactions under these conditions, 3-and 4-pyridyl, and quinolyl aldehydes led to complex mixtures from which the tetrahedral adducts 31, 32 and 33 could not be isolated but were identied spectroscopically in the crude reaction mixtures. 16

Kinetic analysis
Under reaction conditions rst reported by Leeper and since adapted by us and others to give consistent and comparable experimental results, the reaction of the NHCs with heteroaromatic aldehydes were monitored by 1 H NMR in buffered methanol (triazolium salt 20 mM, aldehyde 20 mM, Et 3 N : Et 3 -N$HCl (2 : 1) 90 mM in CD 3 OD at 25°C). 17 The pseudo second order rate constant of tetrahedral adduct formation was measured (k 1 ) as well as the equilibrium constant for adduct formation (K exp ) ( Table 1). The pseudo-rst order rate constant for tetrahedral adduct decay (k −1 ) was calculated based on the measured values for K exp and k 1 . The pseudo-rst order reaction constant for forward reaction of the tetrahedral adduct (k 2 ) was also estimated from the rate of decay of the tetrahedral intermediate once equilibrium for the intermediate formation had been established. 16 It is assumed that this forward reaction Scheme 3 Preparation and characterization of tetrahedral intermediates.
proceeds via the corresponding BI. Although this intermediate cannot be observed directly under these polar protic conditions, the observation of H/D-exchange at C a implicates a carbanionic intermediate. Furthermore, the increases in k 2 observed in studies to date with electron withdrawing substituents on catalysts or aldehyde supports this proton transfer mechanism via a delocalised carbanion (cf. the diaminoenol or BI).
Equilibrium constants for the decay of selected isolated adducts to their respective aldehydes and NHCs (K diss ) under identical reaction conditions were also measured. While performing the experiments, competitive generation of benzoin product in some cases limited the data that could be measured experimentally. For example, with furfural no useable data could be extracted despite 16 and 22 being isolable and so kinetic analysis was not feasible. With pyridyl aldehyde 34, the limited data measured by experiments could be tted using Berkeley Madonna global tting soware to access the rate constants. This tting using Berkeley Madonna was also performed for reactions where the experimental data could be used directly, with the parameters obtained from tting in good agreement with the experimental data in all cases.
Tetrahedral adduct formation (k 1 , k −1 , K exp ) Effect of 3-substituent on aldehyde (R) ( Table 1, entries 1-4 and 6-9). In the context of the previously observed enhanced   a Conditions: triazolium salt 20 mM, aldehyde 20 mM, Et 3 N : Et 3 N$HCl (2 : 1) 90 mM in CD 3 OD. k 1 , k −1 , K exp and k 2 obtained from 1 H NMR analysis, k t 1 , k−1t and K t obtained using Berkeley Madonna tting soware based on experimental data. See ESI for details. b Competitive benzoin reaction prevented the experimental reaction from reaching equilibrium over the reaction course and so experimental data could not be calculated. The rate and equilibrium constants were extracted from experimental data through global tting using Berkeley Madonna. c The reaction proceeded rapidly and individual rate constants could not be calculated or extracted from global tting using Berkeley Madonna. d k 2 could not be measured as no decrease in adduct concentration was observed. reactivity of 2-substituted aldehydes, we proposed 3-substituted pyridine-2-carboxaldehyde derivatives to investigate the effect of additional substitution ortho to the aldehyde functional group in combination with the presence of a ring nitrogen ortho to the aldehyde. In reactions with triazolium 39, the rate and equilibrium constants can be compared when the substituent in the 3-position is varied (34 (R = H), 35 (R = Me), 36 (R = Br), 37 (R = F), Table 1, entries 1-4). Equilibrium constants K exp are up to 20fold larger for non-hydrogen ortho substituted aldehydes (R = H: 2.00 × 10 3 M −1 ; Me: 4.36 × 10 3 M −1 ; Br: 4.03 × 10 4 M −1 ; F: 9.41 × 10 3 M −1 ). This contrasts with the previously reported 2substituent effects in benzaldehydes where a signicant increase in K exp was observed only for 2-heteroatom substituted aldehydes. Breaking each of these equilibrium values down into their constituent rate constants, k 1 and k −1 , the source of the increase in K exp is not the same for each aldehyde. For 35 (R = Me, entry 2), a decrease in k 1 (1.93 × 10 −1 M −1 s −1 (35) vs. 5.88 × 10 −1 M −1 s −1 (34)) was observed, but a corresponding 6-fold decrease in k −1 compared with 34 (4.38 × 10 −5 s −1 (35) vs. 2.94 × 10 −4 s −1 (34)) leads to an overall increase in K exp . A large K exp (4.03 × 10 4 M −1 ) is observed for 36 (R = Br, entry 3) and is a compound effect of large k 1 (3.66 M −1 s −1 ) and a small k −1 (9.09 × 10 −5 s −1 ), while for 37 (R = F, entry 4), the increase in K exp is a result of an increase in k 1 (2.53 M −1 s −1 (37) vs. 5.88 × 10 −1 M −1 s −1 (34)) with approximate maintenance of k −1 (2.69 × 10 −4 s −1 (37) vs. 2.94 × 10 −4 s −1 (34)). Similar trends for the reaction constants involved in tetrahedral intermediate formation are observed for reactions of triazolium 42 (Ar = Mes) with 3-substituted aldehydes 35, 36 and 37 (entries [6][7][8][9]. The observed increase in k 1 for 36 (R = Br) and 37 (R = F) can in part be attributed to an increase in electrophilicity of aldehyde when an electron-withdrawing group is ortho to the aldehyde. Given Br-and F-substituents have closely similar electron withdrawing substituent effects (e.g. Hammett s m = +0.39 (Br), +0.34 (F)) 18 the substantially enhanced k 1 and K exp for 36 (R = Br) points to an additional steric inuence in this case. By twisting out of conjugation with the aldehyde and diminishing the donating effect of the heteroatom lone pair, sterically bulky 2-substituents (such as when R = Br) can additionally increase aldehyde reactivity towards nucleophiles. 19 Steric effects are also revealed in a comparison of k −1 values. The decrease in k −1 for 35 and 36 (R = Me and R = Br) compared with 34 and 37 (R = H and R = F) parallels the observed trend of bulky substituents disfavouring reformation of starting materials from the tetrahedral intermediate.
Overall, these results clearly demonstrate that large 2substituent effects are also observed for heteroaromatic aldehydes, which further enhance the effect of the 2-heteroatom in favouring formation of the tetrahedral intermediate. The largest combined effect is observed for the combination of the pyridyl nitrogen and ortho-bromo substituents with K exp for 36 and triazolium 39 almost 4000-fold larger than for benzaldehyde (Table 1,

entry 3 and Scheme 2).
Position of substituent on pyridine (R vs. R ′ ) (Table 1, entries 1, 2 and 5; 6, 7 and 10). Incorporation of a methyl substituent on the 6-position of the pyridine ring (ortho to the ring nitrogen and meta-to the aldehyde) (38, R = H, R ′ = Me) was investigated in reaction with triazolium salts 39 (Ar = Ph) and 42 (Ar = Mes) (entries 5 and 10). In reaction with 39, 38 (entry 5) gave rate constants (k 1 , k −1 ) and K exp closely similar to 34 (R = R ′ = H entry 1), and therefore signicantly different from 3-methylsubstituted aldehyde 35 (R = Me, R ′ = H, entry 2). For reaction of 38 (R = Me, R ′ = H) with 42 (Ar = Mes) (entry 10), the measured rate and equilibrium constants for intermediate formation (k 1 and K exp ) are again close to those measured for the reaction of 42 (Ar = Mes) with 34 (R = R ′ = H) (entry 6) suggesting that substitution in this position has minimal effect on the equilibrium between starting materials and the tetrahedral intermediate. Overall, substitution ortho to the aldehyde has a substantial impact on rate and equilibrium constants for adduct formation whereas additional substitution ortho to the ring nitrogen has a negligible effect.
In our recent study of the C a -H/D exchange reactions of a large series of twenty bicyclic triazolium salts, 22 a similar trend was observed with higher key rate constants for the 5-fused series (n = 1) and similar, smaller values for the 6-and 7-fused salts (n = 2 and n = 3). Based on X-ray structural data obtained for the twenty triazolium salts and DFT computational evaluation, these changes were attributed to several structural effects including changes in internal triazolyl NCN angle and positioning of the most proximal CH 2 with variation in fused ring size. In the case of C a -H/D exchange reactions, subtle changes were observed with k ex up to 2.2 times larger for n = 1 compared with n = 2. In this study, the effect is magnied with k 1 and K exp in the range of four to ten times larger for n = 1 vs. n = 2 (39 vs. 40 and 42 vs. 43), and smaller but signicant differences observed comparing n = 2 with n = 3 (40 vs. 41). This enhanced effect highlighted by our present results is likely a result of the greater steric demand for the addition to an aldehyde compared to relatively undemanding H/D exchange process.
Effect of heteroatom on fused ring (X) ( Table 1, entries 15 and 17-19). Triazolium salts 45 (Ar = Ph) and 46 (Ar = Mes) based on morpholine were also tested under the model reaction conditions and their reactivity can be compared directly with analogous piperidine-based catalysts 40 (Ar = Ph) and 43 (Ar = Mes). Comparison of 40 with 45 reveals a small but signicant 2fold increase in the equilibrium constant for tetrahedral adduct formation K exp (4.53 × 10 2 M −1 (40) vs. 8.61 × 10 2 M −1 (45)). A similar 2-fold increase in K exp was observed when a methylene group is exchanged for an oxygen atom in N-Mes catalysts 43 and 46 (7.87 × 10 3 M −1 (43) vs. 1.56 × 10 4 M −1 (46)). In both cases, an increase in k −1 was observed, but a greater increase in k 1 led to an overall increase in K exp .

Tetrahedral adduct dissociation (K diss )
To further validate these rate and equilibrium constants, the decay of selected tetrahedral adducts towards equilibrium was studied ( Table 2). Analysis of the 1 H NMR reaction proles for dissociation of selected adducts of aldehyde 35 allowed rate and equilibrium constants of dissociation to be measured (k d , s −1 and K diss , M −1 ) and rate constants for association (k a , M −1 s −1 ) to be calculated. In this analysis, although k a = k 1 and k d = k −1 a distinction has been made to differentiate between the two methods of measurement for either the forward (addition of NHC to aldehyde) or reverse (dissociation of tetrahedral adduct) processes. The observation of closely similar values for k a and k 1 , or k d and k −1 , through starting from different ends of the equilibrium gives condence in the absolute and relative magnitudes of these values. For example, the dissociation rate constant k d (4.54 × 10 −5 s −1 ) of tetrahedral adduct 12 (Table 2, entry 1) is close to the reverse rate constant k −1 (4.38 × 10 −5 s −1 ) of tetrahedral adduct 12 formation (Table 1, entry 2).

Conclusions
In conclusion, measurements of equilibrium and rate constants for the reaction of triazolium NHC precatalysts with heteroaromatic aldehydes to give tetrahedral 3-(hydroxybenzyl)azolium adducts under stoichiometric conditions have been made. Twenty tetrahedral adducts were isolated and fully characterised including X-ray crystallographic analysis for 13. The results obtained from kinetic analysis and tting data show that nucleophilic addition into pyridyl aldehydes is fast compared with existing data for addition to benzaldehydes. Notably, the combined effect of the heteroatom of the heterocyclic aldehyde and an additional substituent both ortho to the aldehydic position result in exceptionally large enhancements in equilibrium constants for tetrahedral adduct formation. In particular, large effects are observed with both 3-halogen (Br, F) and 3methyl substituted pyridine-2-carboxaldehydes, which together substantially favour formation of the tetrahedral intermediate relative to benzaldehyde derivatives. Given this initial adductforming step is common to all NHC-catalysed transformations of aldehydes involving the BI, the accelerated formation of adduct clearly must underpin the preferential reactivity of heteroaromatic aldehydes. Catalyst and aldehyde structure affect the observed kinetics of adduct formation, decay to starting materials and onward reaction to BI. Key observations indicate that increased steric hindrance lead to a reduction in both k 2 and k −1 for large (2,6-disubstituted)-N-Ar groups and sterically demanding aldehyde substituents in the 3-position, but not in the 6-position of the pyridine-2-carboxaldehyde derivatives. A decrease in the forward reaction constants (k 1 , k 2 ) for larger fused rings (n = 2, 3) on the NHC is observed, but an increase in the forward reaction constants is observed upon incorporation of heteroatom in the fused ring. Further work from our laboratories will extend this type of analysis to alternative aldehyde and NHC-catalyst families.

Author contributions
ADS and AOD designed the project. ZD, CMY and JZ carried out the experimental work and analysed the data. AMZS carried out X-ray crystallographic analysis. CMY, ADS and AOD wrote the paper with contributions from all authors.

Conflicts of interest
There are no conicts to declare.