Proton Affinities of N-Heterocyclic Olefins and Their Implications for

Article pubs.acs.org/joc

Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX

Proton Affinities of N‑Heterocyclic Olefins and Their Implications for Organocatalyst Design Robin Schuldt,† Johannes Kästner,† and Stefan Naumann*,‡ †

Institute for Theoretical Chemistry, University of Stuttgart, Pfaffenwaldring 55, D-70569 Stuttgart, Germany Institute of Polymer Chemistry, University of Stuttgart, Pfaffenwaldring 55, D-70569 Stuttgart, Germany

‡

J. Org. Chem. Downloaded from pubs.acs.org by IOWA STATE UNIV on 01/27/19. For personal use only.

S Supporting Information *

ABSTRACT: The proton affinity (PA) of a range of structurally different N-heterocycles with an exocyclic double bond (= Nheterocyclic olefins, NHOs) has been determined using DFT calculations on the BLYP/def2-TZVPP level. It was found that NHOs belong to the upper end of the superbasicity scale, covering PA values from 262 to 296 kcal/mol. Different types of NHOs are compared with each other and with frequently employed organocatalysts. To boost PA, (a) the ability to delocalize the positive charge and (b) steric pressure/ring strain which can be relieved after protonation were identified as key tuning parameters. Importantly, by analyzing PA alongside partial charges and molecular electrostatic potentials, it is shown that an increase of double bond polarization is not a necessary prerequisite for high PA. In contrast, the more basic, more sterically congested NHOs minimize unfavorable interactions by partly pyramidalyzing the nitrogen atoms, rendering the olefinic bond less electron rich and less polarized. These findings are in excellent agreement with experimental evidence on NHO catalysis, not only providing guidelines for a more rational design regarding PA/basicity but also suggesting that NHOs could be specifically tailored toward either nucleophilic or base-type reaction pathways.

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INTRODUCTION

positive partial charge, while the corresponding excess of electron density is located on the exocyclic carbon atom. This electronic situation renders NHOs capable Brønsted bases and strong nucleophiles, which in turn makes them interesting candidates as catalytically active components in a broad range of chemical transformations. In view of these characteristics, NHOs are increasingly employed as organocatalysts, including for example CO2 sequestration,3−9 base-catalyzed alkylations,10 silylation reactions,11 hydroborylations,12 ring-opening polymerization of epoxides13,14 or lactones,15 and the zwitterionic polymerization of acrylates.16 In combination with Lewis acids, NHOs have also performed competently as co-catalysts for polymerizations reactions, enabling novel selectivities and the conversion of challenging monomers.17−22 Further fields of application include the stabilization of unusual oxidation sates or of sensitive compounds23,24 and also generally the employment of NHOs as ligands.25 In the latter case, especially their strong electron donation, ease of preparation and electronic flexibility have been noted;26−31 coordination to metal centers is end-on, as a consequence of the considerable polarization of the double bond. NHOs were even found to tolerate being used as ligands in tungsten complexes active in olefin metathesis.32 In view of these developments, it is all the more surprising that correlations of NHO structure and resulting chemical

As a consequence of their exciting properties, N-heterocyclic olefins (NHOs) have emerged in the past few years as a promising type of novel organocatalyst.1,2 Their chemical behavior is usually assigned to an electron-rich and polarized double bond. Indeed, a mesomeric structure, proposing charge separation, seems to adequately describe the reactivity of NHOs (Scheme 1). Depending on its chemical structure, the N-heterocyclic moiety is more or less capable of supporting a Scheme 1. Mesomeric Structures of Two Different NHOs with Designation of the Olefinic Carbons, Whereby Charge Separation Results in (a) an (Aromatic) Imidazolium Motif or in a Less Stabilized (b) Imidazolinium Moietya

Received: December 18, 2018 Published: January 11, 2019

a

Protonation occurs at C2. © XXXX American Chemical Society

A

DOI: 10.1021/acs.joc.8b03202 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry

Figure 1. NHO structures as investigated in this study. M06-2X/def2-TZVPP calculations have been conducted for compounds 1−6.43,44 The differences were found to be marginal, thus justifying the application of BLYP-type calculations for performance reasons. For a comparison of all three methods, see Table S1. The pyramidalization of the nitrogen atoms was determined according to eq 2:45

behavior have only been assessed on a qualitative level, and even this only to a limited degree. One of the more obvious questions relates to the actual basicity of NHOs. Experimental determination of pKa values has so far been restricted to very few examples.33,34 As a consequence, it is neither fully clear how NHOs compare to other types of basic organocatalysts (such as guanidines, N-heterocyclic carbenes, or phosphazenes) nor how structural variation of the NHO motif exactly impacts this important property. The present work aims to clarify this picture. To this end, proton affinities (PAs) were calculated in vacuo as an indirect measure of basicity for a range of different NHOs. In the following, this data will be used to understand some important trends for intrinsic NHO basicity in the gas phase. Furthermore, structural changes upon protonation will be discussed in detail, and a general comparison to other organocatalysts will be conducted; likewise, it will be instructive to correlate experimental data on catalytic performance with the calculated PAs and to discuss the most promising strategies to manipulate this value by adapting the chemical structure of the NHO.

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3

P(%) =

90°

× 100%

(2)

Thereby, P denotes the pyramidalization in % with the summation being carried out over the bond angles αi (in degrees) of the observed atom. Resulting from three mutually perpendicular p-type atomic orbitals, maximum pyramidalization is achieved for 3

∑ αi = 270° i=1

(3)

The three bond angles before and after protonation have been extracted from the optimized structures, respectively.45 Further analysis of the investigated compounds was performed using Gaussian 16 (B.01).46 To do so, a single point energy calculation in Gaussian 16 has been performed on the B3LYP/def2TZVPP level for the geometries previously optimized by TURBOMOLE. The natural population analysis was carried out using Gaussian internal natural population analysis linked to the NBO program package.47 These calculations were based on the previously executed DFT calculations on the BLYP/def2-TZVPP level for all structures. The extracted NBO charges of the olefinic bond for the NHOs 1−4 are detailed in Table S2. Visualization of the molecular electrostatic potential (MEP) was performed using GAUSSVIEW 6, the graphical interface to Gaussian.48 An isosurface of the electron density at 0.04 au is shown for each structure, color-coded with the electrostatic potential (the color code was chosen from −0.001 to 0.2 au). A complete overview of the corresponding MEP structures is presented in Figures S1−S19.

COMPUTATIONAL METHODS

To determine the PA of structures 1−17, geometry optimizations in the gas phase have been performed for both the NHO itself as well as the protonated derivatives. For this purpose, density functional theory (DFT) calculations using the Becke−Lee−Yang−Parr functional with Ahlrichs redefined triple-ζ double valence polarized basis set (BLYP/ def2-TZVPP) were performed with the TURBOMOLE 7.1. program package,35−38 using dl-find interfaced via chemshell.39−42 According to the definition of PA, for each compound, the corresponding value was obtained from the following relation (eq 1): E PA = E NHO(protonated) − E NHO

360° − ∑i = 1 αi

(1)

To assess the accuracy of the BLYP/def2-TZVPP-level results, analogous calculations on the B3LYP/def2-TZVPP-level as well as B


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RESULTS AND DISCUSSION First, a range of suitable structures was selected for investigation. The corresponding compounds were chosen to reflect the most important NHO types, intentionally including structures which have already been synthesized and applied in catalytic transformations (Figure 1). Thus, this study includes imidazole-derivatives (1−5, 7a, 15−17) as well as NHOs based on benzimidazole (6), triazole (14), and saturated five(7b−10) and six-membered (11−13) heterocyclic ring systems. Also, both “naked” CCH2 moieties (1, 5−8, 12, 14) and substituted exocyclic carbons (C = CR1R2) are considered, while for N-substituents, methyl groups and aryl motifs have been chosen. Based on experimental evidence and qualitative considerations, it was expected to find clear-cut differences between the imidazole derivatives and their saturated counterparts,13−16 as also indicated by calculationderived PAs and kinetic investigations reported by the Mayr group.49 For the imidazole-type NHOs, a higher reactivity is usually observed, which is often linked to the presumed increased basicity compared to the saturated derivatives. This effect is usually explained by a better delocalization of the positive charge in case an imidazolium moiety forms (Scheme 1a) compared to a somewhat reduced stabilization when only the N−C−N motif is involved in delocalization (Scheme 1b). Beyond that, no definite suggestions exist so far, which obviously poses a major obstacle for rational organocatalyst design. In this regard, the calculations conducted in this investigation provide several new and useful insights. Table 1

As can be seen, overall NHOs possess a considerable proton affinity, strongly dependent on the type of heterocyclic backbone, but also noticeably modified by the substituents on the nitrogen atoms and on the exocyclic, olefinic carbon C2. The structurally simple and synthetically readily accessible compound 1 displays a PA of 273.9 kcal/mol; this is fully comparable to typically employed N-heterocyclic carbenes (NHCs).50 Moreover, a simple manipulation of the exocyclic carbon, by introducing one additional methyl group (2) entails an increase of the PA to 279.5 kcal/mol. This further increases when two methyl groups are present (3, 283.6 kcal/mol) and interestingly even more so once the two methyl groups are constrained and “bound back” by incorporating them into a cyclopropane motif (4, 284.7 kcal/mol). Reducing the electron density by attaching two chlorine atoms to the backbone (5) sharply decreases the corresponding value, as must be expected for a conjugated system like this. Indeed, the PA calculated for 5 is the lowest found in this study. While 1−5 all possess Nmethyl groups, the application of mesityl (2,4,6-trimethylphenyl) substituents seems to effect a pronounced increase of PA (1 vs 7a, 273.9 and 282.1 kcal/mol). The same tendency is also observed for the saturated five- and six-membered compounds (7b/8, 11/12), similar to previous reports investigating NHCs.50 For the saturated scaffolds, generally lower PAs result than were observed for the imidazole derivatives. Compound 8, which can be understood as the saturated analogue to 1, is calculated to have a PA of 262.3 kcal/mol, on a level with chlorinated 5. Introducing a dimethyl- (9) or cyclopropane motif (10) analogously entails an increase of the PA, up to 277.9 kcal/mol. Six-membered 11 displays a value of 270.9 kcal/mol, practically identical to the one of its five-membered congener 9. Further, it is interesting to note that a benzimidazole-based backbone (6, 262.4 kcal/ mol) imposes a PA that is very similar not only to the saturated cyclic scaffolds (8, 11) but also to triazole-derived compound 14. Hence, when identical substitution patterns are considered, it is always the imidazole derivatives which achieve the highest PA, that is, 1 > 6 ≈ 8 ≈ 14 and 7a > 12 > 7b and 3 > 9 ≈ 11. Likewise, increasing the degree of alkyl substitution on the exocyclic carbon uniformly increases PA, that is, 3 > 2 > 1 and 9 > 8. In contrast, with identically substituted double bonds and the same N-substituents, NHOs based on benzimidazoles, triazoles, or saturated five- and six-membered rings seem to be quite similar with regard to PA as a particular property. For a rationalization of these results, it is helpful to study not only the NHO structures themselves but also the corresponding protonated species. The most obvious change is found for the olefinic bond. Prior to protonation, which occurs at C2, the original NHO C1C2 bond lengths were calculated to range from 133.7 to 139.0 pm (Table 1). After protonation, values of 148.0 to 156.8 pm are found. This clearly reflects the transition from double- to single bonds and a change in hybridization from sp2 to sp3 for the exocyclic carbon. The calculated bond lengths are in good accordance with data obtained from crystal structures (d(C1C2) = 135.7−136.9 pm (1), 134.2 pm (12))20,51 and can thus be confidently assumed to be sufficiently accurate. However, neither absolute bond lengths nor the absolute or relative changes thereof after protonation can be used as reliable indicators for the PA. This most probably results from the superposition of several factors with partly opposite effects. Indeed, as will be detailed below, the resulting PA cannot be related to a single factor. Likewise, it is no surprise that attempts to correlate PA with 1H or 13C NMR

Table 1. Calculated PA, Corresponding Bond Lengths (Both NHO (CC) and protonated species NHO−H+ (C− C)), and Quantification of Pyramidalization P at the Nitrogen Atoms Prior to Protonation NHO

PA [kcal/mol]

C1C2 bond length [pm]

C1−C2 bond length [pm]

1 2 3 4 5 6 7a 7b 8 9 10 11 12 13 14 15a 15b 16 17

273.9 279.5 283.6 284.7 261.6 262.4 282.1 273.6 262.3 270.4 277.9 270.9 277.0 273.8 263.2 280.6 284.3 289.3 296.1

136.8 136.9 135.9 135.9 136.1 136.0 136.6 135.9 135.7 135.5 133.7 136.0 136.7 137.4 136.3 137.5 137.5 136.8 139.0

149.2 150.0 151.3 148.0 149.2 149.3 149.1 149.5 149.7 151.8 149.2 153.8 150.8 154.0 148.9 149.8 150.0 156.8 150.0

P (N1) P (N2) [%] [%] 0.6 0.2 16.5 4.6 4.2 0.0 0.0 0.3 10.6 26.0 16.0 20.2 0.9 9.0 1.3 0.6 0.1 7.3 3.8

0.7 10.8 20.3 5.6 5.2 0.0 0.0 6.5 13.4 19.3 21.6 5.4 1.1 2.1 0.2 4.7 12.2 9.4 10.6

lists the PAs found for compounds 1−17, alongside some of the more relevant structural parameters, including the CC/ C−C bond length both prior to protonation and afterward, and the pyramidalization45 at the nitrogen atoms in the NHO. A complete set of all data (including Cartesian coordinates of the minima) is provided in the Supporting Information. C


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Figure 2. Visualization of different NHOs (with the calculated PA in square brackets [kcal/mol]) and their protonated congeners.

Figure 3. MEP surfaces for several NHOs (calculated PA given in square brackets [kcal/mol]). Red = strong attractive interaction, blue = strong repulsive interaction. For full data set, see SI.

C2-methyl groups. Significantly, the protonated molecule 3-H+ can release this strain, because the now sp3-hybridized C2 is able to rotate and move its methyl substituents out of plane with the heterocyclic ring system, resulting in a “perpendicular” arrangement (Figure 2) and allowing for a full aromatization of the imidazolium-moiety as indicated by pyramidalization values of now close to 0% (see Table S5). Thus, energetically, compound 3 does profit even more from accepting a proton than 1 or 2 do so, because strain is released and the stabilization gained by aromatization is still pronounced. An NHO such as 1 is already in a more favorable, more conjugated state and consequently stabilizes to a smaller extent upon protonation. Thus, the reason NHO 3 is more prone to accept a proton than 1 is not found in a higher polarization of the double bond; quite conversely, charge separation should be more efficient for 1, because the more distorted heterocyclic ring system of NHO 3 is less able to accommodate a positive partial charge. If this interpretation, relating the increase in PA to the underlying steric congestion, is correct, significant implications for NHO design arise. It would suggest that the frequently

analysis alone, typically showing a significant high-field shift for the olefinic protons and carbons, fail (see Table S4 for a collection of relevant NMR data). Other contributors seem more suitable to understand the resulting PA, especially when considered together. These mainly include (i) the pyramidalization at the nitrogen atoms, (ii) the release of strain upon protonation, and (iii) the molecular electrostatic potential (MEP) of the NHO and NBO-derived partial charges (specifically at the C1 and C2 positions). Thereby, (i) can be seen as an indicator for conjugation and also for the degree of stabilization the molecule gains from protonation, (ii) is identifiable by changes in bond angles and spatial arrangement, and (iii) tells about the electronic situation in the NHO, insofar as the electronrichness and polarization of the olefinic bond is mirrored. If 1, 2, and 3 are considered regarding the pyramidalization of nitrogen, a notable, stepwise increase is observed when going from the uncongested, almost fully planar 1 (CCH2 moiety) to 3 (CC(CH3)2, Table 1)). The out-of-plane positioning of the nitrogen atoms in der latter case is a reaction to unfavorable steric interaction between the N-methyl and the D


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present in 4, is considerably more strained than the corresponding methylcyclopropane moiety formally existing within 4-H+ (Scheme 2). Upon protonation, the inner bond

cited idea of manipulating the polarity of the double bond as dominant tuning site for the reactivity/basicitywith the implicit assumption of increasing both by increasing charge separationis a too simplistic concept for rationally designing NHO organocatalysts. The major electronic effects seem to be aromatization and charge delocalization, while strain relief recommends itself as a strong buttressing factor if a high PA is targeted. Aromatization of the corresponding conjugated acid is a well-documented strategy to enhance the basicity of neutral organic compounds, as has, for example, been described for cyclopropenimines or troponimines.52,53 This is further substantiated when taking partial charges into account, as calculated by the NBO methodology (see Table S2). For compound 1, a value of q = −0.687 for C2 is found,54 which decreases to −0.417 and further to −0.100 when 2 and 3 are considered, respectively. This obviously reflects the substitution pattern on the exocyclic carbon, but taken together with the very similar olefinic bond lengths in all three cases (Table 1), it suggests that polarization is not increased when adding alkyl groups in the C2 position nor is there evidence for an excessively large electron excess on this carbon atom in 3. Indeed, it should be noted that a “fixed” charge separation (right side of the mesomeric formulations in Scheme 1) should manifest in the occurrence of C2pyramidalization and an increase in bond length since the double bond character would be weakened. Interestingly, this phenomenon seems to be developing for 17, the NHO with the highest PA (see below). The marked differences of 1 and 3 also occur when considering the corresponding MEPs (Figure 3), supporting the reasoning given above. Since the MEP mirrors the potential to which a test probe (H+) is subjected along a certain surface of the molecule, the underlying electronic situation is revealed. Regions with strong, attractive interactions (color coded red) accordingly signify high electron density. For compound 1, the site most attractive to a proton is clearly the double bond in the vicinity of C2; the considerable polarization of the double bond is obvious. In contrast, distorted, nonplanar compound 3 shows very different characteristics. The double bond is less polarized, and the area of the strongest attractive interaction is shifted toward the N−C−N moiety. This is in full accordance with the previously noted pyramidalization at nitrogen for this molecule; as a consequence of the distortion, conjugation is severely weakened. The olefinic bond can therefore not engage in a meaningful partial charge separation and considerable electron density accumulates at the sp3-like nitrogen atoms, highlighting that this molecule is on its way to becoming a classical nitrogen base. It is also instructive to discuss NHO 4 in an analogous manner. On account of its constrained cyclopropane substitution, the steric interaction with the N-methyl groups is reduced, coherently resulting in a significantly smaller degree of pyramidalization compared to 3 (4.6%/5.6% vs 16.5%/ 20.3%). Likewise, the MEP calculated for this NHO (Figure 3) shows a behavior much more similar to 1 and 2 than it is to 3, namely the most prominent attractive potential located on the olefinic bond near C2. After protonation, the heterocyclic ring is then fully planar, while again the exocyclic carbon rotates its substituents out of plane (Figure 2). Thus, if only pyramidalization is considered, the high PA may initially seem somewhat surprising, since it should be lower than that of 3. However, an additional strain-releasing factor must also be taken into account: A methylenecyclopropane subunit, as

Scheme 2. NHO 4 and Protonated Version Thereofa

a

Formally, a methylenecyclopropane moiety with its allylic C−H bonds transforms into a methylcyclopropane motif.

angle at C2 changes from 62.7° to 58.8°, while bond lengths C2−Cring increase from 148 to 153 pm. Intriguingly, it has been found that the decrease in ring strain in methylcyclopropane is a consequence of a higher Cring−H bond dissociation energy; for the methylenecyclopropane the same protons are allylic and relatively weakly bound.55 When accepting a proton, NHO 4 thus additionally stabilizes by a decrease of the ring strain within the cyclopropane motif itself. The latter factor seems significant enough to overall result in the highest PA among compounds 1−14. A very similar trend is found for compounds 9 and 10, where likewise a decoration with cyclopropane significantly lifts the PA. Regarding pyramidalization of NHOs with other backbones, it is noteworthy that nonstrained 6 and 14 are broadly planar, while the saturated N-heterocyclic rings show a strong out-ofplane distortion. This is even true for noncongested 8 (10.6%/ 13.4%) and most pronounced for compound 9 (26.0%/ 19.3%). It should be noted that for the saturated, fivemembered ring-systems, this is not only a reaction to potential steric congestion (interaction with C2-methyl, 9) but also a general feature to avoid eclipsed arrangement of the C−H bonds in the backbone (8). A planar, fully conjugated N−C−N moiety, however, entails exactly that. After protonation, all of these structures show de facto full planarization at the nitrogen atoms, suggesting that the positive charge is delocalized and overcompensates for this unfavorable arrangement. Interestingly, the N-aryl moieties, as present in 7b and 12, seem to enforce a much more planar geometry of the N-heterocyclic ring in the NHO already (Table 1), to which the mesityl groups are oriented in an almost perpendicular manner. This effect is most probably caused by the four methyl groups in the ortho positions, which “lock” the planar conformation (see Figure S8 and S13); a strong distortion from planar geometry would generate unfavorable steric interaction of one mesityl moiety with the other or with the N-heterocyclic ring itself. Regarding the calculated MEPs, again a consistent picture emerges (Figure 3). For 6, the attractive potential residing in the olefinic bond is only weakly pronounced, comparable to the electron-poor compound 5, and accordingly both NHOs display a very similar PA (262.4 kcal/mol vs 261.6 kcal/mol). Likewise, the strongly distorted 8 shows a shift of the highest attractive potential toward the nitrogen atoms, fully in line with the above discussion of NHO 3. Similarly, the incorporation of the exocyclic C2 in a cyclopropane moiety with concomitant increase of PA is mirrored by the corresponding MEP (10, Figure 3). Above considerations provide some guidelines on how to effectively manipulate the PA of NHOs by chemical E


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The Journal of Organic Chemistry modification. If a high respective value is desired, it is thus rewarding to select (a) an imidazole-based backbone, ensure (b) an electron-rich double bond, create (c) steric congestion which is released upon protonation and if possible, and employ (d) ring strain to provide a further boost for increasing PA. We thus designed and calculated compounds 15−17, to showcase the above recommendations. To further underline the marked influence of steric congestion, NHOs 15a and 15b provide informative examples. The former carries an isopentyl-substituted C2, and the latter a tert-butyl group in the same position. While both show a comparatively high PA, it is evident that the formally larger isopentyl group is less effective for this purpose; clearly, the tert-butyl moiety is able to exert a much more direct steric pressure on the N-methyl groups, which is coherently also mirrored in the pyramidalization at nitrogen (0.6%/4.7% vs 0.1%/12.2%, Table 1). The trend in PA is thus in full agreement with the previous discussion, and it should be noted that 15b, albeit bearing only a single substituent on C2, is on par with cyclopropane-decorated 4 by making beneficial use of increased steric congestion. The next example, compound 16, was chosen to embody the combined influence of steric congestion and electron-donating substituents (satisfying the recommendations (a−c)). This NHO bears methoxy groups on its backbone and on its N-aryl moieties, while at the same time C2 is dimethylated. The resulting PA is high, and with a calculated value of 289.3 kcal/ mol surpasses all compounds discussed earlier. Structurally, a notable pyramidalization can be observed (7.3%/9.4%), even though the mesityl groups are oriented almost perpendicular to the N-heterocyclic ring. The protonated version 16-H+ is fully planarized, and the methyl groups on C2 show the expected orientation above and below the ring plane (Figure S18). The electron density provided by the methoxy groups stabilizes the positive charge and presumably engenders a more electron-rich double bond. Finally, compound 17 shall be considered. This NHO shows some interesting features which lead to the exceptionally high PA of 296.1 kcal/mol, putting it almost among the ranks of “hyperbases”, which are defined to have a PA of 300 kcal/mol and above.56 If the structural parameters of this compound are considered (Table 1), a modest pyramidalization (3.8%/ 10.6%) and a relatively long CC double bond are noted (139 pm), the latter being the longest for the complete set of NHOs investigated in this work. A further important property is the pronounced torsional angle that can be observed between the N-heterocyclic ring plane and the one encompassing the cyclopentane moiety (50°, Figure 4). The unfavorable steric interactions in this molecule seem not to be sufficiently relieved by nitrogen pyramidalization alone, additionally requiring this strong torsion along the central NHO axis. Hence, the π-overlap is disturbed, and the double bond-character reduced. This manifests in the relatively long C1C2 bond and also in a beginning pyramidalization of the C2 carbon itself (1.3%), signaling a partial, if weak, sp3 character and the presence of excess electron density with lone pair character, nicely mirrored by the corresponding MEP. Consequently, protonation not only allows for planarization/aromatization but also for a tremendous strain relief; in 17-H+, the two ring planes are oriented in a fully perpendicular manner. A final factor boosting PA in this NHO is found in ring strain relief (cyclopentane-moiety); it is notable that already in the NHO, the inner bond angle at C2 is

Figure 4. Visualization of NHO 17. Note the significant torsion along the CC axis. Right: The highest attractive potential for H+ is located on C2 (MEP).

109°, further highlighting the strongly distorted formal sp2hydridization at this carbon atom. After protonation, this further decreases to 106.8°, while bond lengths C2−Cring increase from 155 and 156 pm to 158 and 159 pm. In 17H+, the less constrained cyclopentane moiety can thus relax and reduce unfavorable interactions.

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COMPARISON WITH THE PA OF OTHER ORGANOCATALYSTS AND CORRELATION WITH CATALYTIC BEHAVIOR PA has been determined for numerous other organobases, both by way of calculations and through experiments.56,57 This provides a convenient database to put the results found for NHOs in a broader context. From such comparison, it follows that even the mildest NHOs possess a higher PA than some of the most frequently employed organobases. Thus, for typically employed cyclic amidines and guanidines, such as 1,8diazabicyclo[5.4.0]undec-7-ene (DBU, Scheme 3) or 1,5,7triazabicyclo[4.4.0]dec-5-ene (TBD), corresponding values of 247−253 kcal/mol and 249−254 kcal/mol have been determined.56−60 Interestingly, for the well-established imidazole-2-ylidenes among NHCs, a PA of 262−275 kcal/mol was calculated, depending on the nitrogen substituent (Scheme 3).50 Archetypical IMes (270.4 kcal/mol) is on par with saturated 9, while IAd (274.9 kcal/mol) is comparable to compound 1. Abnormal NHCs (aNHCs), on the other hand, easily achieve PAs in the range of 280−290 kcal/mol;50,61 accordingly, it can be concluded that readily accessible NHOs such as 3 are superior to many frequently applied NHCs regarding this particular property, while the more advanced structures (4, 15−17) can well compete with abnormal NHCs, which is remarkable in itself. It should be noted that the order of basicity for NHCs, as determined by the pKa of their conjugated acids, is very different from the one suggested by the PA calculations for NHOs. For the former, saturated and especially ring-expanded NHCs are more basic than imidazole2-ylidenes.62 For NHOs, it is the other way round with the imidazole derivatives being superior with respect to this property. Finally, a comparison with phosphazenes is instructive. These compounds have been developed as neutral, organic molecules with exceedingly high basicity but low nucleophilicity.63 Four examples shall be considered (Scheme 3). For tBu-P4, the probably best known and most widely used phosphazene base, a PA of 297.5 kcal/mol has been found; reducing the number of P(V)-atoms while retaining identical substitution patterns accordingly lowers the corresponding F


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Scheme 3. Left: Frequently Employed Organopolymerization Catalysts and Right: Divergent Behavior of NHOs 1 and 3 for the Polymerization of GBL

case, exclusively anionic polymerization seems to occur.20 Thus, in this case, NHO 1 acts as nucleophile, while compound 3 displays base-type behavior. This was explained by a presumed higher pKaH-value of 3 relative to 1, an assumption which is strengthened by the findings in this study: ΔPA for both NHOs is 9.7 kcal/mol, which is substantial. However, a more complete explanation would also consider the steric effects leading to a distortion of NHO 3 in difference to planar 1. It is proposed that a compound like NHO 3 acts as a base because the increased steric congestion exerted by the additional C2-methyl groups leads to a double effect. For one, basicity is increased (suggested by the higher PA as discussed above), and second, the polarization of the double bond is decreased (as evident from N-pyramidalization and analysis of partial charges). Combined, both factors will render a basic pathway more attractive than zwitterionic polymerization mechanisms relying on the nucleophilicity of the organocatalyst. Nucleophilicity is a kinetic concept, and as mode of action much more suitable for a structure like 1, which is nonhindered and additionally possesses a strongly polarized double bond and a lower PA compared to 3. It should be noted that similarly, for PO it was found that employment of NHO 3 completely suppressed any zwitterionic polymerization.13 As a final note, it should be stressed that NHOs are structurally identical with so-called deoxy-Breslow intermediates, which are frequently encountered in NHC-mediated organo(polymerization)catalysis. These intermediates have been identified as crucial for a number of important applications, including polymerization or dimerization of Michael-acceptor systems such as methyl methacrylate and many others.65−71 Since the (re)generation of deoxy-Breslow intermediates/NHOs is a key aspect in these transformations, it can be assumed that the same factors which regulate the PA will also play a role in these cases. Interestingly, Mayr has investigated some NHO structures for their reactivity toward electrophiles and found that the nonsaturated imidazolederivatives are much more reactive than their saturated counterparts.49 This is in full agreement with the results presented in this work.

values to 288.8 kcal/mol (tBu-P3), 274.4 kJ/mol (tBu-P2), and 260 kcal/mol (tBu-P1), all data via B3LYP(I)-level calculations.56,64 This renders tBu-P4 comparable to NHO 17, tBuP3 equivalent to NHO 16, and tBu-P2 very similar to 1. Most of the NHOs which have actually been synthesized (such as 1, 3, 6, 8−12) are thus in the range of P2-bases or just below, regarding PA and the presumed basicity in solution. While it must be stressed that gas phase results, such as PA, cannot be used as generally valid predictors for reactions in solution, it is very tempting to correlate these findings with experimental evidence, not least because the PA data obtained fit very well to results of catalytic transformations involving NHOs, mainly polymerizations. For example, the difference between saturated and nonsaturated NHOs has surfaced in a very clear manner in a number of instances. The polymerization of propylene oxide, for example, succeeds with the latter type of NHO organocatalysts (1, 3) to result in a nicely defined polyether.13 In contrast, the saturated compounds with identical substitution patterns, such as 8, do not yield any polymer even after prolonged reaction times. Similarly, the organopolymerization of N,N-dimethylacrylamide is successful when NHO 1 or 3 are employed, while on the other hand, it fails for compounds 6 and 8.16 This nicely fits to the step change found for PA values discussed above when using NHOs with imidazole-derived backbones. The polymerization of lactone and carbonate monomers illustrates this further. While the more reactive and presumably more basic NHO 3 polymerizes δ-valerolactone in an uncontrolled, extremely rapid manner and likewise does so for trimethylene carbonate (TMC), the much milder organocatalyst 9 consumes TMC in a slow polymerization with living characteristics.15 ΔPA between both compounds is 13.3 kcal/mol (56 kJ/mol), and therefore of a magnitude to potentially explain these differences. Perhaps most importantly, the findings presented here also provide a novel and more satisfying explanation for the strikingly different polymerization behavior of 1 and 3 regarding lactone monomers. For γ-butyrolactone (GBL), it was found that application of compound 1 entails a zwitterionic polymerization, initiated by direct attack of the NHO on the carbonyl carbon of the cyclic ester, followed by ring-opening.20 NHO 3, in contrast, polymerizes the same monomer by way of an anionic mechanism, via enolization (= deprotonation) of the monomer (Scheme 3). Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-ToF MS) analysis not only found the expected, different end groups but also highlighted the degree of selectivity with which these alternative polymerization pathways are operative; indeed, for 1, only zwitterionic species were identified, while in the latter

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CONCLUSION The PA of 19 different N-heterocyclic olefins (NHOs) has been determined, using DFT calculations on the BLYP/def2TZVPP-level. It was found that NHOs firmly belong on the upper end of the superbasicity scale, covering a PA range of 262−296 kcal/mol. A comparison with other, frequently employed organocatalysts shows this to be sufficient to compete with strongly basic NHCs, easily surpassing the G


Article

The Journal of Organic Chemistry corresponding PA of typical amidines or guanidines. The specific values strongly depend on the chemical structure of this special class of olefins. As major tuning sites, (a) the backbone of the N-heterocyclic ring, (b) the steric interaction between the N- and C2-substitutents, and (c) ring strain/ torsional strain have been identified. For identical substitution patterns, imidazole-derived NHOs always have a higher PA than found for saturated backbones, or benzimidazole- and triazole-based compounds. This can be explained by formation of an aromatic imidazolium cation upon acceptance of a proton. Less stabilized protonated NHOs can delocalize the positive charge only over the N−C−N motif. Steric pressure constitutes another decisive factor for boosting PA. Even for small substituents, such as N-methyl and C2-methyl, best conjugation (= fully planar molecule) cannot be realized anymore for imidazole-derived NHOs such as 3. To reduce the unfavorable interaction, the nitrogen atoms in the heterocyclic ring start pyramidalizing, which breaks conjugation but enables the N-substituents to point above or below the ring system. After protonation, the structure becomes fully planar, also aided by the fact that the now sp3-hybridized C2-atom can rotate and move its substituents out of plane. A third contributor to buttress PA was found by incorporating the olefinic carbon atom C2 in a cyclic system, such as a cyclopropane motif. In the latter case, the protonated molecule can not only aromatize and reduce steric congestion but also profits from reduced ring strain. Notably, steric effects can be strong enough to even promote the less favored, saturated NHOs to achieve a PA in the range of imidazole-based NHOs, providing a synthetically convenient tool for designing PA and basicity of NHOs. In more extreme cases, steric congestion can lead to torsion along the axis of the olefinic bond, which is duly lengthened, losing π-overlap. The NHO for which the highest PA of 296.1 kcal/mol was calculated is an example for the latter case, coming close to the threshold defined for so-called hyperbases. For compounds 1−4, it was also demonstrated that increasing PA does not develop alongside a growing polarization of the double bond. In contrast, the increasing basicity relies to a great extent on steric congestion, and the resulting distortion from planar geometry disfavors partial charge separation. This nicely fits experimental findings for “nucleophilic”, sterically uncongested NHOs (1) and “basic” NHOs (3), indicating that the findings presented in this work might not only help in designing the basicity of NHO organocatalysts but also to influence the reaction pathways, an important feature in view of the frequently encountered base/ nucleophile dualism in organopolymerization reactions.

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Stefan Naumann: 0000-0003-2014-4434 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors gratefully acknowledge funding by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) within the collaborative research center (CRC) 1333 (project number 358283783). Also, the state of BadenWürttemberg is acknowledged for support through bwHPC (INST 40/467-1 FUGG (JUSTUS cluster)).

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b03202. Total energies, further tabular data (PDF) Cartesian coordinates of compounds 1−17 and protonated derivatives (ZIP)

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REFERENCES

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Johannes Kästner: 0000-0001-6178-7669 H


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Proton Affinities of N-Heterocyclic Olefins and Their Implications for

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