The Role of the Fused Ring in Bicyclic Triazolium Organocatalysts: Kinetic, X-ray, and DFT Insights.

Bicyclic triazolium scaffolds are widely employed in N-heterocyclic carbene (NHC) organocatalysis. While the incorporation of a fused ring was initially for synthetic utility in accessing chiral, modular triazolyl scaffolds, recent results highlight the potential for impact upon reaction outcome with the underpinning origins unclear. The common first step to all triazolium-catalyzed transformations is C(3)-H deprotonation to form the triazolylidene NHC. Herein, we report an analysis of the impact of size of the fused (5-, 6-, and 7-membered, n = 1, 2, and 3, respectively) ring on the C(3) proton transfer reactions of a series of bicyclic triazolium salts. Rate constants for the deuteroxide-catalyzed C(3)-H/D-exchange of triazolium salts, kDO, were significantly influenced by the size of the adjacent fused ring, with the kinetic acidity trend, or protofugalities, following the order kDO (n = 1) > kDO (n = 2) ≈ kDO (n = 3). Detailed analyses of X-ray diffraction (XRD) data for 20 triazolium salts (including 16 new structures) and of computational data for the corresponding triazolylidene NHCs provide insight on structural effects of alteration of fused ring size. In particular, changes in internal triazolyl NCN angle and positioning of the most proximal CH2 with variation in fused ring size are proposed to influence the experimental protofugality order.

Introduction

Since Ukai first utilized naturally occurring thiazolium salt 1, or vitamin B1, to catalyze the benzoin reaction of aldehydes,[1] and later seminal studies by Breslow in establishing the catalytic mechanism,[2] a broad range of related transformations catalyzed by different heterocyclic azolium salts continue to be investigated.[3,4] As organocatalysts, azolium salts have been used to catalyze a diverse spread of reactions, including the benzoin and related acyloin reactions,[2,5] Stetter reaction,[6] cycloadditions,[7] dearomatizations,[8] among many others. Although a range of heterocyclic azolium classes have been employed in organocatalysis, triazolium precatalysts 2 are most often utilized[9] (Figure ). Typically, the reactions are initiated by a deprotonation step, which involves in situ conversion of the azolium salt 2 to the reactive N-heterocyclic carbene (NHC) 3/ylide 3′. In particular, chiral bicyclic triazolylidene scaffolds, initially developed by Knight and Leeper,[10] have been widely investigated, with the development of modular syntheses allowing improved stereoselectivities.[3a] A range of fused ring triazolium salt precatalysts have been employed, with those derived from pyrrolidinone,[11] morpholinone,[12] or oxazolidinone[13] scaffolds (4–6, respectively) common.

Figure 1

(a) Structure of thiamin 1 (vitamin B1); (b) C-(3) deprotonation of triazolium precatalyst 2; (c) pyrrolidinone-, morpholinone-, and oxazolidinone-derived triazolium salts 4–6.

Recent investigations have recognized that the role of the fused ring is not solely limited to providing a structural scaffold for chiral modification toward asymmetric catalysis. Gravel and co-workers reported that the chemoselectivity of the benzoin condensation could be influenced by a simple change in both the size and composition of the fused ring for bicyclic triazolium salts 7k, 8k, and 9k (Figure a).[14] Piperidinone-derived triazolium salt 8k (n = 2) with a N-pentafluorophenyl substituent was shown to catalyze highly chemoselective cross-benzoin reactions between aliphatic and aromatic aldehydes. Although still yielding the same major product, analogous pyrrolidinone- and ε-caprolactam-derived triazolium salts, 7k (n = 1) and 9k (n = 3), showed significantly reduced chemoselectivities under these reaction conditions. This remains one of the few examples of a chemoselective cross-benzoin reaction that is catalyst- rather than substrate-controlled. Notably, selectivity and yield were shown to be invariant to either base or solvent choice. In a follow-on computational study supported by 1H NMR and crossover experiments, Gravel, Legault, and co-workers explored the origin of the chemoselectivity differences for 7k, 8k, and 9k, although this study was not extended to triazolium salts with additional N-aryl substituents.[14b] The superior selectivity observed for the piperidinone-derived catalyst 8k was attributed to the kinetic control of reaction conditions. Furthermore, it was suggested that the steric interactions of proximal methylenes on the catalyst backbone with the aldehyde could play a significant role in obtaining chemoselectivity.

Figure 2

(a) Previous work: demonstration by Gravel et al. of catalyst control of product selectivity in the cross-benzoin reaction by variation of triazolium fused ring size. (b) This work.

Despite the enormous current interest in NHC-organocatalysis, an understanding of chemoselectivity (as represented by the cross-benzoin reaction) remains one of the key unsolved challenges, and so the influence of the fused ring is potentially of importance across many transformations. As an initial deprotonation step is common to the majority of these transformations, we herein report an analysis of the impact of fused ring size on the C(3) proton transfer reactions of a series of triazolium salts (Figure b). Following on from our earlier studies,[15] we undertook a hydrogen–deuterium exchange study to evaluate the effect of ring size on the kinetic acidities, or protofugalities,[16] of the C(3)-hydrogens in a series of bicyclic triazolium ions. Experimental second-order rate constants for deuteroxide-catalyzed H/D-exchange, kDO (M–1 s–1), could be used in Hammett structure–activity analysis in addition to providing estimates of C(3)-H pKa values. We have performed X-ray diffraction and computational studies to afford additional insight. Despite the substantive literature focused on triazolium catalysis, there is no report to our knowledge comparing structural data for a large series of triazolium salts. We have analyzed experimental X-ray diffraction data for 20 triazolium salts (Figure b), which includes 16 previously unreported X-ray crystal structures. In addition, a DFT computational evaluation of the structures of these 20 triazolium ions and corresponding triazolylidenes has been performed. These data provide new insights into the role of fused ring size on the initial proton transfer step common to all triazolium-catalyzed transformations.

Results and Discussion

Hydrogen–Deuterium Exchange Kinetic Studies

Hydrogen–deuterium or hydrogen–tritium exchange has long been used as a method to estimate the kinetic lability of protons attached to carbon[17] and to provide insight into factors influencing carbon acidity. For catalytic applications, the knowledge of rates of proton transfer between active species, and the corresponding activation barriers, is equally as important as pKa. In early studies, several groups reported rate constants for the base-catalyzed exchange of the C(2)-H of thiamin 1 providing initial evidence for the role of the conjugate base NHC/ylide as the active form of catalyst.[17c−17f,18] The later isolation and structural characterization of a range of NHCs by Bertrand and Arduengo,[19] including thiazolylidenes[20] and triazolylidenes,[21] provided further support for their relatively long lifetimes versus many other carbene classes. We have previously reported H/D-exchange kinetic studies for a range of conjugate acids of NHCs/ylides.[15a−15d] This included rate-pD profiles for the C(3)-H/D exchange of pyrrolidinone-derived triazolium salts 7a–c,i,k with 5-membered fused rings.[15a−15c]

In order to analyze the effect of ring size on proton transfer, analogous H/D-exchange kinetic studies have been performed for piperidinone-derived triazolium salts 8a–c,k (with 6-membered fused rings) and for ε-caprolactam-derived triazolium salts 9a–c,k (with 7-membered fused rings). To ensure consistency and accuracy, hydrogen–deuterium exchange experiments for 7a–c,k are repeated herein and showed excellent agreement with our earlier data.[22] The kinetic methods utilized (section S1.4, Supporting Information) were identical to those employed in our previous work. First-order rate constants for H/D-exchange were determined in aqueous solution at a range of pD values with ionic strength I = 1.0 (KCl) at 25 °C and with tetramethylammonium deuteriosulfate as internal standard. Using 1H NMR spectroscopy, the decrease in the area of the C(3)-proton of each substrate could be quantified over time. Figures S1–S12 include representative spectral overlays of reaction progress for 7a–c,k, 8a–c,k, and 9a–c,k. The reactions were analyzed in the pD range of 0.5–3.5, because outside of this range the exchange reactions were too fast (pD > 3.5) or slow (pD < 0.5) for NMR kinetic analysis. During these experiments there was no decrease of other NMR resonances or appearance of additional signals, confirming that no side reactions, such as hydrolysis or decomposition of triazolium salt substrates, were occurring under these conditions. The observed pseudo first-order rate constants for deuterium exchange of the C(3)-proton, kex (s–1), were obtained from the slopes of semilogarithmic plots (Figures S13–S24) of reaction progress against time according to eq , where f(s) is the value of the fraction of unexchanged substrate. Tables S1–S12 summarize all first-order rate constants, kex (s–1), as a function of pD, and Figures S25–S28 include the corresponding log kex–pD profiles. No corrections were applied for data acquired in buffer solution, because in all previous studies no evidence of buffer catalysis was observed.Figure compares the log kex–pD profiles for the deuterium exchange reactions of 7c, 8c, and 9c with those for 7k, 8k, and 9k. For N-4-fluorophenyl triazolium salts 7c, 8c, and 9c, good linear fits of log kex–pD data to eq were observed; in eq , kDO (M–1 s–1) is the second-order rate constant for deuteroxide-catalyzed exchange, Kw the ion product of D2O at 25 °C,[23] and γDO the activity coefficient for deuteroxide ion under our experimental conditions. Data for all other triazolium salts studied herein also showed good linear fits to eq (Figures S25–S27) with the exception of 7k, 8k, and 9k. This increase in log kex with pD, and first-order dependence on deuteroxide ion, is consistent with a single mechanism for deuteroxide-catalyzed deuterium exchange as shown in Scheme . In this mechanism, deprotonation of the triazolium salts 7–9 by deuteroxide results in the formation of a complex between NHCs 7′–9′ and a molecule of HOD (in Scheme , the ylidic resonance structures of NHCs 7′–9′ have been excluded for clarity). Subsequent reorganization of 7′–9′·HOD to 7′–9′·DOL (L = H or D) to allow for delivery of deuterium, followed by deuteration, leads to exchange product 10.[15a,15d,24] Owing to the large excess of bulk solvent D2O over substrate, the deuteration step is effectively irreversible; thus, kex reflects rate-limiting formation of solvent-equilibrated NHC from the triazolium salt and deuteroxide ion.

Figure 3

Comparison of pD rate profiles of C(3)-H/D exchange for triazolium salts 7–9c and 7–9k in D2O solution at 25 °C.

Scheme 1

Mechanism for C(3)-H/D Exchange for Triazolium Salts 7–9

As a result of a change from a simple first-order dependence on deuteroxide ion at lower pD values, and hence from a slope of unity, log kex–pD data for N-pentafluorophenyl salts 7k, 8k, and 9k instead show excellent fits to eq . The altered dependence of log kex on pD is consistent with the onset of alternative pathways for deuterium exchange, which we have discussed in detail previously.[15a,15b,15f] The most likely mechanistic explanation is a pathway via N(1)-deuteration at lower pD values allowing for hydrogen–deuterium exchange of the N(1)-deuterated dicationic triazolium salt (Scheme S2, section S1.4.4.4, Supporting Information). The additional terms in eq (versus eq ) include k′DO (M–1 s–1), the second-order rate constant for deuteroxide-catalyzed C(3)-H/D exchange of the dicationic salt, and KaN1, the equilibrium constant of N(1)-protonation. The extent of dominance of this alternative pathway at lower pDs is dependent on pKaN1. The similar overall behavior observed for 7k, 8k, and 9k suggests that the biggest influence on the onset of alternative H/D-exchange mechanisms is the N-aryl substituent rather than the size of the fused ring within the triazolium salt.

Table summarizes values of the second-order rate constant for deuteroxide-catalyzed exchange, kDO (M –1s–1), for all triazolium salts studied herein. By definition, the second-order rate constant, kDO (M–1 s–1), is the observed kex value in 1 M DO– solution (pD ≈ 14). Experimentally, hydrogen–deuterium exchange for all triazolium ions is many orders of magnitude too fast to directly monitor in 1 M DO– (half-lives ≈ nanoseconds); thus, kDO values are obtained by assessment of a range of kex values at lower pD’s as described above. The comparison of reactivities toward deprotonation by a common base, kDO, allows for comparison of the kinetic acidities, or protofugalities,[16] of the C(3)-hydrogens in the series of bicyclic triazolium ions. As DO– is the relevant conjugate base of water and of similar basicity to widely used alkoxide ions, and with an increasing general focus on organocatalysis in more sustainable solvent media such as water,[25] it is an appropriate choice as a reference base.

Table 1

Summary of Second-Order Rate Constants for C(3)-H/D Exchange (kDO) for 7a–c,k (n = 1); 8a–c,k (n = 2); 9a–c, 9k (n = 3) and Calculated C(3)-H pKa Values

triazolium salt	n	R =	kDO (M–1 s–1)a	kDOreld	pKae
7a	1	4-OMe	4.55 (±0.36) × 107	2.26	17.7
7a			4.20 (±0.23) × 107b	2.09	17.8
8a	2		2.11 (±0.18) × 107	1.05	17.9
9a	3		2.01 (±0.20) × 107	1	18.0
7b	1	H	6.99 (±0.18) × 107	2.12	17.5
7b			6.82 (±0.13) × 107b	2.07	17.5
8b	2		3.43 (±0.15) × 107	1.04	17.8
9b	3		3.29 (±0.15) × 107	1	17.8
7c	1	4-F	8.97 (±0.27) × 107	2.04	17.4
7c			8.66 (±0.11) × 107b	1.97	17.4
8c	2		5.00 (±0.31) × 107	1.14	17.7
9c	3		4.39 (±0.16) × 107	1	17.7
7k	1	–F5	3.52 (±0.37) × 108c	0.87	16.8
7k			6.82 (±0.25) × 108b,c	1.69	16.5
8k	2		4.16 (±0.19) × 108	1.03	16.7
9k	3		4.04 (±0.19) × 108	1	16.7

This work.

Values of kDO (M–1 s–1) obtained previously.

The error quoted for 7k is that obtained based on the overall fit to eq for all of the data. The larger variance from our previous value for 7k is due to the unavoidably small number of data points in the region of unit slope. The kDO value obtained previously is deemed more reliable owing to the lower overall error in fitting to eq as a result of having a greater number of data points.

Calculated as kDOrel = kDO/kDO.

pKa values calculated using experimental kDO values (vide infra).

Obeying the common trend observed previously,[15a,15c,15d] electron-withdrawing N-aryl substituents increase kDO, regardless of the size of the fused ring, with a span of ∼26-fold across the series in Table . Thus, triazolium salts 7k, 8k, and 9k bearing the strongly electron-withdrawing N-pentafluorophenyl substituent have the highest kDO values, whereas analogues 7a, 8a, and 9a with the electron-donating N-4-methoxyphenyl substituent have the lowest protofugalities. Electron-withdrawing N-aryl substituents destabilize the cationic triazolium carbon acid 7–9 relative to the formally neutral NHC conjugate base 7′–9′ (Scheme ), thus favoring the deprotonation process.

Table also includes krel (= kDO/kDO) values, which allow for a comparison of the effect of the fused ring for a given N-aryl substituent. Notably, despite the distance from C(3)-H, the size of the fused ring clearly alters the protofugalities of the triazolium salts. In all cases, the 5-membered ring fused triazolium salts 7 have the highest rate constants for deuteroxide-catalyzed exchange, while the 6- and 7-membered ring fused salts 8 and 9 have lower values (n = 1 > n = 2 ≈ n = 3). The differences observed are relatively small (krel ≤ 2-fold); however, they are substantially outside experimental error, with added confidence provided from the observation of the same trend for different N-aryl substituents. In addition, the first-order rate constants for H/D-exchange (kex), which are used to calculate kDO, are consistently higher for triazolium salts 7 compared to 8 and 9 (see log kex–pD profiles Figures S25–S28).

Figure S29 includes a Hammett analysis of protofugalities (kDO) as a function of fused ring size. In the case of the N-pentafluorophenyl substituent, a σ substituent constant calculated by Taft[26] is utilized. Hammett ρ values, obtained as slopes of the correlations in Figure S29, are positive for the three series as expected for a process favored by electron-withdrawing substituents. The Hammett substituent dependencies demonstrated by 5-, 6-, and 7-membered fused rings are closely similar in magnitude (ρ = 0.65, ρ = 0.65, 0.67). Notably, these experimental ρ values are all less than unity, indicating a similar but smaller N-aryl substituent dependence than for the reference acid dissociation of benzoic acids despite having the same three bond distance from the acidic hydrogen to the ipso-aryl carbon. For 7–9, the inherent stabilization provided by the three nitrogen atoms within the central NHC heterocycle could decrease the dependence on the nature of the N-aryl substituent. Furthermore, the closely similar experimental ρ values suggest that the N-aryl substituent effect is independent of the fused ring.

X-ray Crystallographic Studies

During the syntheses of bicyclic triazolium salts for our kinetic studies, we determined 20 single-crystal X-ray structures (Figure ), which includes 16 previously unreported structures (section S1.6, Supporting Information, and CCDC 2124937–2124950; 2124952–2124958). The crystals of triazolium salts 7a–g, 7i–k, 8a–c, 8i, and 9a–b, 9k were obtained by slow evaporation of methanol. The growth of single crystals of 7h, 8k, and 9c suitable for single-crystal X-ray diffraction analysis was performed via a modified high-throughput encapsulated nanodroplet crystallization (ENaCt) approach (section S1.6.1).[27]

Figure 4

Summary of the single-crystal X-ray structures of 20 triazolium salts determined herein. (*Electron deficiency ordering based on Hammett substituent parameters; Table S13.)

The X-ray crystallographic data was analyzed for structural insight on the role of the size of the fused ring and potential structure–kinetic activity trends. The bond lengths and bond angles of individual triazolium salt core structures are summarized in Tables S17 and S18. In general, triazolium salts with the same fused ring size were found to result in similar core structural parameters irrespective of the N-aryl substituent. Within each series (n = 1 (11 structures), n = 2 (5 structures), and n = 3 (4 structures)) the average bond angles and bond lengths of triazolium salts were calculated and are summarized in Tables and S19. The differences in average angles and distances between series (n = 1 vs n = 2 and n = 2 vs n = 3) are also included in Table .

Table 2

Summary of Average Bond Angles and Distances of Triazolium Salts 7a–k (n = 1); 8a–c, 8i, 8k (n = 2); 9a–c, 9k (n = 3) Obtained from Single-Crystal X-ray Structural Analysis

	triazolium salts: average angles and distancesb
		n = 1	n = 2	n = 3	n = 1 vs n = 2c	n = 2 vs n = 3d
bond angles (deg)a	CβC5N4	110.6 [0.5]	122.2 [0.5]	124.2 [0.5]	11.6	2.0
	C5N4Cα	113.7 [0.4]	125.6 [0.7]	127.6 [0.3]	11.8	2.0
	N4C5N1	111.9 [0.2]	111.3 [0.6]	110.7 [0.2]	–0.6	–0.6
	C3N4C5	107.4 [0.2]	106.9 [0.5]	106.9 [0.3]	–0.5	0.0
	N1N2C3	111.9 [0.4]	111.7 [0.4]	110.8 [0.7]	–0.2	–0.9
	N2C3N4	106.1 [0.3]	106.8 [0.3]	107.4 [0.3]	0.8	0.6
	C5N1N2	102.8 [0.3]	103.3 [0.1]	104.1 [0.4]	0.6	0.7
distance (Å)	H1H2e	3.06 [0.04]	2.76 [0.02]	2.49 [0.03]	–0.31	–0.26
	H1H3e	3.29 [0.05]	3.09 [0.03]	3.37 [0.05]	–0.19	0.28
torsion angle (deg)	H1C3CαH2e	43.6 [1.9]	38.2 [2.3]	1.7 [0.9]	–5.4	–36.5
	H1C3CαH3e	69.6 [1.6]	70.9 [2.2]	105.3 [1.6]	1.3	34.4

Average of bond angle values obtained by X-ray diffraction measurement for triazolium salts 7a–k (n = 1); 8a–c, 8i, 8k (n = 2); 9–c, 9k (n = 3).

Standard deviation of average values is shown in square brackets.

Difference = Average(n = 2) – Average(n = 1).

Difference = Average(n = 3) – Average(n = 2).

The Cα hydrogens with the shorter and longer through-space distances from H1 are labeled as H2 and H3, respectively.

Focusing first on average bond angles in the triazolyl and fused rings, it can be observed that significant changes in bond angles occur between the 5-, 6-, and 7-membered ring series (Table and Figure ). With expansion of the size of the fused ring (from 5- through to 6- and 7-membered ring series), bond angles at the fusion point within the fused ring increase, and this impacts the bond angles in the adjacent triazolyl ring. Changing from 5- to 6-membered rings (n = 1 to 2) results in larger increases for the CβC5N4 and C5N4Cα average angles by 11.6° and 11.8°, with smaller further increases of 2.0° for both angles upon changing from 6- to 7-membered rings (n = 2 to n = 3, Figure a). As a result, three of the five angles of the central triazolyl ring decrease (C3N4C5, N4C5N1, and N1N2C3; Figure b), while the remaining two angles increase (N2C3N4 and C5N1N2; Figure c) owing to the increasing fused ring size.

Figure 5

Bond angles (a) CβC5N4 and C5N4Cα increase; (b) N1N2C3, C3N4C5, and N4C5N1 decrease; and (c) C5N1N2 and N2C3N4 increase as n increases.

The observed angular changes at the fusion point within the fused ring upon moving from the 5- to 6-membered ring series are substantially larger (∼11–12° from n = 1 to n = 2) than between the 6- and 7-membered ring series (∼2° from n = 2 to n = 3), which parallels the observed effects of ring size on protofugality. Irrespective of N-aryl substituent, 5-membered ring fused triazolium salts 7 have the highest kDO values, while 6- and 7-fused salts 8 and 9 have smaller but similar values (n = 1 > n = 2 ≈ n = 3). The angular changes within the triazolyl ring appear more similar with increasing fused ring size; however, its significance cannot be unequivocally ascertained owing to the smaller changes involved. Of most relevance to the H/D exchange studies herein, there is a small but significant increase in the N2C3N4 angle at the acidic C(3)-H position from n = 1 to n = 3 in all cases. This ranged from an increase of 1.8° for 7–9a, 1.8° for 7–9b, 1.3° for 7–9c, and 1.0° for 7–9k.

We also analyzed the through-space distances from the C(3)-hydrogen (H1) to the most proximal methylene hydrogens (Cα-H2 and H3) with changing fused ring size, but note the caveat of a greater uncertainty in hydrogen atom positioning from standard X-ray diffraction analysis. The through-space distances are reproduced in our DFT analysis of all the triazolium ions (vide infra), giving confidence in these values. The Cα hydrogens with the shorter and longer distances from H1 are labeled as H2 and H3, respectively (Table ). These H1H2 and H1H3 distances are used as one measure of differences in the magnitude of the steric effect of the proximal methylene group as a function of changing fused ring size. The average H1H2 distance decreases from 3.06 to 2.49 Å with expansion of the size of the fused ring indicative of a corresponding increased steric effect of the methylene from 5- through to 6- and 7-membered ring series. This parallels the overall observed decrease in protofugality, and rate constants for deuteroxide-catalyzed C(3)-H/D exchange, with increasing fused ring size presumably owing to greater steric hindrance of the approach of DO– to H1 when closer to H2.

The through-space distances of H1 from H2 and H3 are linked with changes in the torsion angles H1C3CαH2 and H1C3CαH3, respectively. Notably, CαH2 is almost coplanar with C3H1 when n = 3 as the average H1C3CαH2 dihedral angle is only 1.7°. By contrast, CαH2 is not coplanar with C3H1 when n = 1 and n = 2 with similar average H1C3CαH2 torsion angles of 43.6° and 38.2° for the 5- and 6-membered series. We postulate that the almost coplanar relationship of C3H1 and CαH2 (n = 3), in addition to the shorter through-space distance of H1 and H2 in this case, may contribute to an increased steric hindrance on the approach of the base and a resultant decrease in protofugalities. While these through-space distance and torsion angle trends align with the overall decrease in protofugalities from n = 1 to n = 3, clearly additional factors are needed to explain the observation of higher kDO values for the 5-fused triazolium series with similar, smaller values for 6- and 7-fused salts 8 and 9 (n = 1 > n = 2 ≈ n = 3).

Finally, alteration of the triazolium N-aryl group changes the N1N2CγCδ dihedral angle in the solid-state structure (Tables S17 and S18). Typically, N-aryl groups without ortho-substituents are close to coplanar with the central triazolium ring and have N1N2CγCδ dihedral angles of ∼0°. Unsurprisingly, the introduction of bulky ortho-substituents on the N-aryl ring increases N1N2CγCδ with the largest dihedral angle of 91.2° observed for di-ortho-propylphenyl-substituted 7h. Alteration of the N-aryl group is external to the triazolium core structure and removed from the fused ring. Thus, changes in the N1N2CγCδ dihedral angle are mainly dictated by the N-aryl group rather than fused ring size (n = 1, 2, 3). This is consistent with the observation of closely similar ρ-values in our Hammett analysis of kDO for 7, 8, and 9, respectively.

DFT Calculations

To further understand the key structural factors underpinning observed differences in protofugalities with fused ring size, the 20 triazolium salts 7–9 in Figure and their corresponding carbenes 7′–9′, were studied computationally (Supporting Information, section S2). The B3LYP and M062X functional with the polarized diffuse split-valence 6-311++g(d,p) basis set and the polarizable continuum model (PCM) with the solvent option of water were used in all cases.[28] Several conformations of each molecule as starting geometries were optimized to find the most stable (lowest energy) geometry. The vibrational frequencies of these most stable geometries were then calculated at the same level of theory and revealed no imaginary frequencies, confirming them as true minima. The calculated bond angles and bond lengths of the core bicyclic structures of the 20 individual triazolium salts 7–9, and corresponding carbenes 7′–9′, are listed in Tables S21–S24 and S28–S31. The lowest-energy conformations calculated computationally for the triazolium ions 7–9 matched the solid-state experimental X-ray structures. Pleasingly, the trends in computed average angles and distances for the triazolium series 7–9 (Table S25 and S26) also match closely with the experimental values in Table . To our knowledge, while there is a published X-ray crystal structure for a 2,4,5-triphenyltriazolylidene,[29] there are no reported experimental structural data for triazolylidenes 7′–9′. The excellent computational reproduction of experimental trends for the fused ring effect in the triazolium series 7–9 gives confidence in a similar analysis of only computational data for the corresponding triazolyl NHCs 7′–9′.

The average bond angles of triazolylidenes 7′–9′ obtained by calculation are summarized in Tables , S32, and S33. For a given size of the fused ring, bond angles within the heterocyclic ring are significantly influenced by conversion of the triazolium conjugate acid 7–9 to the corresponding triazolyl carbene 7′–9′. The largest changes in average bond angle is for N2C3N4, which decreases by ∼6° upon formation of the carbene (Table versus Table ).

Table 3

Summary of Average Bond Angles and Distances of Triazolylidenes 7′a–k (n = 1); 8′a–c, 8′i, 8′k (n = 2); 9′a–c, 9′k (n = 3) Obtained from DFT Calculation (M062X)

	triazolyl carbene: calculated average angles and distancesb
		n = 1	n = 2	n = 3	n = 1 vs n = 2c	n = 2 vs n = 3d
bond angle (deg)a	CβC5N4	111.1 [0.0]	122.9 [0.0]	124.5 [0.1]	11.9	1.6
	C5N4Cα	112.7 [0.1]	124.1 [0.1]	124.7 [0.1]	11.5	0.5
	N4C5N1	110.9 [0.1]	110.1 [0.1]	110.0 [0.1]	–0.8	–0.1
	C3N4C5	111.6 [0.1]	110.8 [0.2]	110.8 [0.1]	–0.8	0.0
	N1N2C3	115.9 [0.3]	115.4 [0.3]	115.3 [0.3]	–0.5	–0.1
	N2C3N4	99.6 [0.2]	100.5 [0.2]	100.6 [0.3]	0.9	0.1
	C5N1N2	102.1 [0.2]	103.2 [0.3]	103.3 [0.3]	1.1	0.2
distance (Å)	C3H2e	2.92 [0.00]	2.69 [0.00]	2.53 [0.00]	–0.22	–0.16
	C3H3e	3.05 [0.00]	2.91 [0.00]	3.18 [0.00]	–0.14	0.28
torsion angle (deg)	N1C3CαH2e	50.6 [0.1]	42.1 [0.3]	2.9 [0.3]	–8.5	–39.2
	N1C3CαH3e	85.4 [0.1]	82.6 [0.2]	121.5 [0.3]	–2.7	38.8

Average of bond angle values obtained by DFT calculation (M062X) for triazolylidenes 7′a–k (n = 1); 8′a–c, 8′i, 8′k (n = 2); 9′a–c, 9′k (n = 3).

Standard deviation of average values is shown in square brackets.

Difference = Average(n = 2) – Average(n = 1).

Difference = Average(n = 3) – Average(n = 2).

The Cα hydrogens with the shorter and longer distances from C3 are labeled as H2 and H3, respectively.

Closely similar effects are observed upon increase in fused ring size for the bicyclic triazolyl carbenes 7′–9′ as observed for the triazolium ions 7–9. Changing from 5- to 6-membered fused ring series (n = 1 to 2) results in large increases in the average CβC5N4 and C5N4Cα angles of the triazolylidenes 7′–9′ (11.8° and 11.4°, respectively), with smaller further increases of 1.6° (CβC5N4) and 0.6° (C5N4Cα) upon changing to 6- and 7-membered series (n = 2 to n = 3). Three of the five angles of the central triazolyl ring decrease (C3N4C5, N4C5N1, and N1N2C3), while the remaining two angles increase (N2C3N4 and C5N1N2) owing to the increasing fused ring size. From XRD data, the average N2C3N4 angle of triazolium salts 7 with n = 1 equals 106.1° (±0.3°), and this number increases to 106.8° (±0.3°) and 107.4° (±0.3°) with n = 2 and 3 for 8 and 9. From computational data for the corresponding NHCs 7′–9′ there is a similar increase in the average N2C3N4 angle from 99.6° (±0.2°) for n = 1 to 100.5° (±0.2°) and 100.6° (±0.3°) for n = 2 and n = 3.

X-ray structural analysis allowed for an evaluation of the distance of the most proximal methylene hydrogens of the fused ring (Cα-H2 and H3) from the C(3)-H1, and changes in the dihedral angles H1C3CαH2 and H1C3CαH3, with changing fused ring size in the triazolium series 7–9. Similar conclusions can be drawn from an analysis of the computational data for the triazolylidenes 7′–9′ in this case represented by the through-space distances of H2 and H3 to the carbenic C(3)-center and torsional angles N1C3CαH2 and N1C3CαH3 (Table ). Again, the methylene hydrogens H2 and H3 are closer to the carbenic position (C3) for the largest fused ring size (n = 3). Using these through-space distances and torsion angles as one measure of the steric effect of the most proximal methylene on the fused ring suggests that the steric impediment to approach of another reagent (e.g., DO–) to either the triazolium or carbene is largest when n = 3 and falls off for the smaller fused rings sizes (n = 2 ∼ n = 1).

As the structural and computational data discussed thus far relate only to the lowest-energy conformations of the triazolium ions and triazolylidenes, we have additionally evaluated the role of conformational flexibility in the fused ring through DFT modeling (section S2.5). By fixing the torsion angle between C3H1 and CαH2 for 7–9b and between N1C3 and CαH2 for 7′–9′b, the energy changes caused by conformation in the fused ring in the vicinity of the carbenic position could be evaluated (Tables S35–S40). The Boltzmann distribution of conformer mole fraction can then be obtained from the energy difference compared with the lowest-energy conformation (Figures S51 and S52). These plots clearly highlight the favored coplanar conformation of Cα-H2 and the carbenic position for 9b and 9′b (n = 3), whereas for 7/7′b (n = 1) and 8/8′b (n = 2) the minimum energy preference is for a larger torsion angle of 35–42°. Despite having different minimum energy starting points, the energy-torsion angle profiles for all structures probed are essentially superimposable after applying starting point corrections (Figure S53).[30]

NCN Angle Effects on Proton Transfer

In our previous H/D-exchange studies we observed substantial decreases in kDO with increase in the internal NCN angle of the NHC. For example, protofugalities for imidazolium ions 10 and 11, which are the conjugate acids of imidazolyl NHCs, are 3–8 orders of magnitude higher than for tetrahydropyrimidinium ions 12. In the imidazolyl case the internal NCN angles within the five-membered heterocyclic ring are substantially smaller than within the six-membered ring of 12 (Figure ). Specifically, comparing two examples with N-alkyl substituents, 11 and 12, for an increase in NCN angle of ∼13° there is a corresponding drop in kDO of 720-fold. Similarly, comparing 12 and 13 with N-Pr substituents, an increase in NCN angle of ∼7° is accompanied by a drop in kDO by ∼50-fold. Although other factors, including the number and type of NHC heteroatoms, aromaticity, and N-substitution, influence protofugalities, the NCN angle changes are clearly also important. We previously argued that an enforced increase in internal NCN angle through alteration of heterocyclic ring size is better accommodated by the conjugate acid (azolium ion) than the conjugate base (NHC), thus contributing to a decrease in acidity.[15d] This argument is supported by closely similar trends for carbene proton affinity (PA) measurements with higher PAs observed for NHCs with larger ring sizes (Figure ).[15e]

Figure 6

Decrease in protofugality (kDO) with increasing NCN angle.[15d,31]

Figure 7

Increase in proton affinity (PA) with increasing NCN angle.[15e,32]

Although substantially smaller in the present case, the increase in N2C3N4 bond angle (by ∼2°) at the acidic position with changing fused ring size from n = 1 to n = 3 also correlates with decreases in kDO (kDOrel ≤ 2). The increase in N2C3N4 angle with changing fused ring size is observed consistently for different N-aryl substituents, supporting the generality of this trend.

In general an increase in angle toward 180° at a carbene center is associated with an increase in p-character of the nonbonding orbitals bearing the negative charge. Similarly, in the present case the small increase in NCN bond angle moving from n = 1 to n = 3 could be qualitatively associated with a concomitant increase in p-character, or decreased s-character, of the hybrid orbital at the carbenic center.[33] Parallels can be drawn with the common textbook explanation for the increase in carbon acidity along the alkane (sp3C-H, pKa ∼ 45–70), alkene (sp2C-H, pKa ∼ 40–45), and alkyne (sp C-H, pKa ∼ 20–25) hydrocarbon series, where the negative charge formed upon deprotonation is more stable in an orbital of greater s-character.[34] Using this argument, we can speculate that the higher protofugalities of the 5-fused triazolyl series might result from increased s-character at the C(3)-position stemming from smaller NCN angles relative to the 6- and 7-fused series.

Estimation of Carbon Acid pKa Values

There is an increasingly large body of work on the conjugate acid pKa’s of NHCs in a range of solvents, including water, acetonitrile, and DMSO, in addition to related gas-phase acidities and proton affinities.[15a−15d,24,32b,35] Several approaches may be employed to access these carbon acid pKa values, which we have reviewed previously.[15e] In aqueous solution, the main difficulty associated with the direct determination of conjugate acid pKa values of NHCs is the well-established leveling effect. Owing to the substantially higher basicities of most NHCs relative to the conjugate base of solvent (HO–), quantitative deprotonation of solvent occurs.

In the determination of aqueous carbon acidities of weakly acidic species, one solution long-employed to circumvent this problem is the calculation of pKa from the rate constants for the forward and reverse directions of the proton transfer equilibrium.[36] We and others have previously employed this kinetic method for the determination of carbon acid pKa values for deprotonation at C(3) for a series of triazolium salts including 7 using eq derived for Scheme .[15a−15d,24] In this equation, kHO (M–1 s–1) is the second-order rate constant for deprotonation at C(3) by hydroxide ion, which may be calculated from the corresponding kDO value using a value of kDO/kHO = 2.4 for the secondary solvent isotope effect on the basicity of HO– in H2O versus DO– in D2O. As discussed previously,[15a,15d] the absence of significant general base catalysis of deuterium exchange provides good evidence that the reverse protonation of the triazol-3-ylidene NHC by water is equal or close to the limiting rate constant for the physical process of dielectric relaxation of the solvent (kHOH ≤ kreorg = 1011 s–1). Rate constants of this magnitude are challenging to access experimentally, generally requiring femtosecond transient absorption spectroscopy; however, values for the dielectric relaxation of water have been determined reliably.[37] Because the main error in pKa determination using this method is associated with the value assumed for kHOH, these pKa values provide upper limit estimations.

Scheme 2

Equilibrium for Acid Dissociation of Triazolium Ions

Using the kDO values determined herein, and by application of eq , we have calculated pKa values for triazolium salts 8a–c,k with 6-fused rings and 9a–c,k with 7-fused rings (Table ). Owing to the ∼2-fold effect of fused ring size on kDO, and the logarithmic relationship to pKa in eq , the resulting pKa values for a given N-aryl substituent are closely similar. These triazolium pKa’s in the 16.7–18 range are ∼4 and 6 units below typical aqueous values for diaryl- and dialkylimidazolium ions, respectively, whereas only ∼1–2 units below typical N-alkylthiazolium pKa’s.[15a−15d,24] The overall effect of the central ring heteroatoms on pKa is larger than either N-aryl or fused ring substituent effects. The influence of fused ring size on kinetic acidities or protofugalities, however, is significantly larger than on pKa. Thus, rates and half-lives of NHC generation by C(3)-deprotonation of the conjugate acid, which is of direct relevance to catalysis, will be significantly influenced by the nature of the fused ring size in the bicyclic triazolium precursor.

Conclusion

In conclusion, this work has probed the effect of the size of the fused rings (5-, 6-, and 7-membered; n = 1, 2, and 3 respectively) within a range of bicyclic triazolium salts on their kinetic acidities, or protofugalities. Rate constants for the deuteroxide-catalyzed H/D-exchange of triazolium salts, kDO, were observed to be significantly influenced by the size of the adjacent fused ring, with the trend following the order kDO(5-membered ring, n = 1) > kDO(6-membered ring, n = 2) ≈ kDO(7-membered ring, n = 3). Hammett ρ values, obtained as slopes of Hammett correlations of kDO values with varying NHC N-aryl substituent, were positive for the three series (5-, 6-, and 7-membered rings, n = 1–3) consistent with a deprotonation process favored by electron-withdrawing substituents. Hammett N-aryl substituent dependencies were found to be closely similar (ρ = 0.65, ρ = 0.64, 0.67). Detailed analyses of X-ray diffraction structural data and computational analysis for 20 triazolium salts/triazolylidenes provide insight on the structural effects of altering fused ring size, which could be aligned with observed effects on kDO. The most proximal methylene of the fused ring is closest and almost coplanar with the carbenic center when n = 3, indicative of a greater steric effect; this parallels our observation of a decrease in rates of deprotonation by DO– when n = 3. Changing from 5- to 6-membered fused ring (n = 1 to 2) results in significant increases (by ∼11–12°) in the CβC5N4 and C5N4Cα angles within the fused ring, with smaller further increases of ∼2° upon changing from 6- to 7-membered ring (n = 2 to n = 3). A resultant change in internal angles in the adjacent NHC ring is also observed. In particular, the resulting ∼2° increase in internal NCN angle is consistent with a drop in acidity (lower kDO values) with increased fused ring size. Finally, carbon acid pKa values of the bicyclic triazolium salts were estimated using a kinetic method.

Given the prevalence of bicyclic structures in NHC organocatalytic scaffolds and their importance for many C–C bond-forming reactions, we hope this work provides quantitative and structural insight into the role of a simple incremental change in the number of methylenes in the fused ring. Clearly, for the proton transfer step between a triazolium salt and triazolyl carbene in aqueous solvent, the size of the fused ring size is important, with five membered fused rings (n = 1) giving significantly higher rates of deprotonation. Ongoing studies in our laboratories are focused on kinetic analysis of the role of the fused ring size in later reaction steps in triazolium-catalyzed benzoin and related acyloin reactions.