Sulfonimide or Sulfonamide? - American Chemical Society

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Molecule VI: Sulfonimide or Sulfonamide? Sten O. Nilsson Lill* and Anders Broo Predictive Science, Pharmaceutical Development, AstraZeneca, Pepparedsleden 1, SE-431 83 Mölndal, Sweden S Supporting Information *

ABSTRACT: The tautomerism of molecule VI, a benchmark system for crystal structure predictions, has been investigated by the use of computational chemistry. Ab initio and density functional calculations including dispersion corrections show that monomers of molecule VI strongly (11 kcal mol−1) prefer to exist as sulfonamide tautomer, while remarkably the equilibrium is shifted toward sulfonimide tautomers in larger aggregates due to formation of stronger hydrogen bonds for the imide tautomer.

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form I a very rare eclipsed conformation is found.12 In the different blind test studies on VI, the predictions were made on the sulfonimide tautomer (Figure 2). When we looked into the

INTRODUCTION In recent years, notable progress has been made in the ability of crystal structure predictions (CSP).1−3 The introduction of the Cambridge Crystallographic Data Centre (CCDC) blind tests4 significantly catalyzed the development of computational protocols to predict the most stable crystal structure of a molecule.3,5−7 The most successful predictive approach to date is probably the method developed by Neumann and coworkers, where a molecule-unique force-field is tailored to reproduce dispersion-corrected density functional theory (DFT-D) data.1,8−11 In the second CCDC blind test, molecule VI (6-amino-2-(phenylsulfonylimino)-1,2-dihydropyridine) was introduced (Figure 1).5

Figure 2. Sulfonimide and sulfonamide tautomers of VI.

literature of sulfonimides we found a large amount of studies also on the possible tautomerism between sulfonimides and sulfonamides (Figure 2)14,15 and found it interesting to extend this analysis also to molecule VI. In all three (I, II, and III) polymorphs of molecule VI, the sulfonimide tautomer has been observed. Forms I and III share the same hydrogen bond pattern (synthon B) characterized by N1−H···O−, N8···HN7 bonds to two neighboring molecules, while in form II synthon A is observed with N1−H···N8−, O··· HN7 bonds to the same neighbor. However, in the crystalline form II, the sulfonamide tautomer may also be important due to the proton location on the pyridine nitrogen N1 forming the intermolecular hydrogen bond to the sulfonimide nitrogen N8 (Figure 3, left).12 If the proton rather would be fully transferred to N8, one would instead have the sulfonamide tautomer (Figure 3, right) although within the same dimer unit. Obviously, this small proton shift changes the formal hybridization at N1 and N8 and could have an effect on the delocalization of electrons in the pyridine ring and, more importantly, the directionality and strength of the hydrogen bonds involved. Desiraju and co-workers have previously discussed the difference in hydrogen bond strengths between

Figure 1. Molecule VI.

There was no success in the crystal structure predictions of VI in the original report; however, later studies have shown the predictive power of recent methodology for this molecule.10,12,13 In the 2001 quest, form I (Z′ = 1) of molecule VI was considered, but later, the structures of form II (Z′ = 2) and form III (Z′ = 1) have been determined using single crystal X-ray diffraction.10,12,13 In the most recent study by Leusen and co-workers, form I is predicted to be the most stable polymorph while form II and III are both ca. 0.9 kJ mol−1 less stable according to the Neumann approach.10 A similar conclusion was drawn by Roy and Matzger based on solventassisted polymorphic transformation experiments, where relative free energies of 0, 0.44, and 0.23 kcal mol−1 were determined for I, II, and III, respectively.13 With the different stable polymorphs of VI discovered, a large interest in its inherent structure has started to flourish.12,16 For example, in © 2014 American Chemical Society

Received: August 19, 2013 Revised: July 16, 2014 Published: July 21, 2014 3704

dx.doi.org/10.1021/cg500916u | Cryst. Growth Des. 2014, 14, 3704−3710

Crystal Growth & Design

Article

P21, C2/c, Pbca, Pnma, Pna21, Pbcn, P1, Cc, C2, and Pca21). Singlepoint PBE-D2 calculations on 22 unique polymorph candidates were performed using CASTEP as described above. Crystal structure comparisons were made using the Crystal Packing Similarity tool in Mercury 3.1 based on a coordination sphere of 15 nearest neighbors.27 CSD-ids of the crystal structures used in this study are UJIRIO (form I), UJIRIO02 (form II), and UJIRIO05 (form III).

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RESULTS AND DISCUSSION Initially, we wanted to confirm that our computational methodology was able to reproduce the stability difference between the different known polymorphs of VI but also that our predicted crystal structures matched the experimentally known structures. Therefore, we used the molecular conformers from forms I−III and generated predicted polymorph landscapes with the method described in the Computational Details. Dispersion-corrected DFT calculations with CASTEP were then used to calculate the relative energies of our predicted structures. The details of the results from the crystal structure predictions are given in the Supporting Information. By the use of dispersion-corrected DFT optimizations with CASTEP, we predict that form I is the most stable polymorph, while forms II and III both are 0.34−0.35 kcal mol−1 less stable. This is in very good agreement with the earlier predictions and experimental results as described in the Introduction. Also, our predicted crystal structures are found in good correspondence with the experimental structures (RMS15 = 0.10−0.22 Å). Thus, both predicted structures and their calculated relative energies with the current approach is found valid and appropriate for studying the effect of tautomerism for molecule VI. Both the experimental crystal structure form II, observed to be a sulfonimide tautomer (I1-cryst), and a sulfonamide tautomer crystal structure (A1-cryst) built by elongating the N1−H bond in the direction of N8 were optimized with DFT-D using CASTEP. Two different optimization strategies were considered, either with a flexible or a fixed unit cell. In both cases two separate stable structures were located with a strong preference (∼4−5 kcal mol−1) for the experimentally observed sulfonimide tautomer. To further support this, we also performed B3LYP-D2 calculations resulting in an energy difference of 4.3 kcal mol−1. The energy difference between the optimized crystal structures of the tautomers could be caused by different packing interactions, but the root-mean square deviation of heavy atoms (rmsdheavy‑atoms) for the two unit cells is as small as 0.114 Å, indicating that it is only the local effect of the proton tautomerism that causes the 5 kcal mol−1 energy difference, although the unit cell dimensions were allowed to be flexible. To further evaluate this, we performed a crystal structure prediction with the GRACE packing machinery9 using the asymmetric unit (Z′ = 2) of the CASTEP optimized structure of the amide A1-cryst, repacking the structure within 13 space groups and thus generating 22 unique polymorph candidates. These were compared with the X-ray crystal structure of form II of VI using the Crystal Packing Similarity tool in Mercury based on a coordination sphere of 15 nearest neighbors.27 Among the 22 polymorph candidates, the most stable polymorph according to the DFT-D2 calculations (Scheme S1, Supporting Information) was found to give the best structural overlap (rmsd15 = 0.152) with the experimental structure. This shows that the effect of the proton transfer is only local and does not result in another packing motif that is more stable, although among the 22 investigated polymorph candidates other motifs were discovered (Supporting Informa-

Figure 3. Sulfonimide (left) and sulfonamide (right) dimers of VI in form II.

forms I and II12,16 and synthesized and crystallized a set of phenylsubstituted analogues of VI, but in all their cases, which cover both forms I and II, the proton was observed at the pyridine nitrogen, i.e., a sulfonimide. In contrast, Chen and coworkers synthesized another analogue of VI, and here the observed structure is a sulfonamide.17 Of particular interest is also sulfapyridine, a closely related compound, which features a crystal structure with both the imide and amide tautomers present.18 Moreover, Henry reported on a 25:75 distribution for the sulfonimide/sulfonamide crystal structures available in the literature.15 Thus, there is significant experimental evidence that both tautomeric forms are possibly obtainable. However, to the best of our knowledge the tautomerism and elucidation of the proton preference in parent VI has not previously been fully addressed. We therefore initiated a computational study to at first investigate the preferred location of the proton in the crystal structure and second if the same tautomer preference is seen in the monomer and dimer of VI as in the crystal structure. Molecule VI is considered as one of the benchmark molecules in the field of CSP, and therefore, it is of importance to understand both its crystal structures and its inherent structure in detail. The object of finding the right tautomer has recently been highlighted in the keto/enol study for barbituric acid.19

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COMPUTATIONAL DETAILS

Monomers and dimers were optimized using M06/6-31+G(d,p) as implemented in Jaguar 8.0.20 M06 was chosen due to its wellestablished performance for both hydrogen bonds and dispersion interactions. Single-point calculations were performed using PBE, PBEh, PBE0, B3LYP, ωB97xD, M06-2X, B2PLYPD, or MP2 using Gaussian0921 employing the same basis set. In addition, tests were done using M06/cc-pvtz(-f) in Jaguar and M06/6-31+G(d,p) with a larger numerical grid (grid = ultrafine) in G09. Additionally, SCSMP2/def2-TZVP and SCS-MP2/aug-ccpvtz calculations using Turbomole22 were performed. For the latter, 42 occupied orbitals were frozen. Solvent effects were evaluated using PBF as implemented using Jaguar with either benzene (ε = 2.28) or DMSO (ε = 47.24). Dispersion corrections (D2 or D3-BJ) to PBE and B3LYP were calculated using the DFT-D3 code.23 Crystal structures were optimized using the PBE functional included in CASTEP.24 D2 dispersion corrections implemented in CASTEP were included. On the fly, pseudopotentials with a reciprocal space representation and an energy cutoff of 600 eV were used and with a SCF tolerance of 1 μeV/ atom as energy convergence cutoff. The k-point separation was set to 0.05 Å. Geometry optimization convergence was reached when energy < 20 μeV/atom and max force < 0.05 eV/Å. PBE has previously been found to give very good solid-state structures, especially for hydrogen bonded complexes.25 B3LYP-D2 calculations were also made in CASTEP using norm-conserving pseudopotentials. CSP was performed using an in-house force field26 and the GRACE packing machinery.9 A large number of Z′ = 2 trial crystal structures were generated in the 13 most common space groups (P21/c, P1̅, P212121, 3705



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support this we investigated the energy difference between the tautomers using a larger basis set, several DFT functionals, and MP2 (Table S1, Supporting Information). In all cases we observed that A1 is clearly more stable (11−16 kcal mol−1) than the I1 conformer observed in the crystal. To ensure that this is not an effect of local conformer energies, a conformer search of the sulfonamide and sulfonimide monomers was performed. The sulfonamide preference was confirmed although a more stable (∼4−5 kcal mol−1) sulfonimide conformer (I2, Scheme 1) was found having a weak intramolecular hydrogen bond between N1−H and O10. Thus, in the crystal structure there is a preference for the invacuum less stable isomer I1, and clearly there must be a strong compensation mechanism for this energy penalty, otherwise in the crystal there would be sulfonamide tautomers. But what gives this stabilization? One key observation to answer this is the influence of the polarizing environment on relative energies of the isomers. Although in a crystal the effects from the environment are not isotropic, it is informative to see how the relative energies are affected by a general polarization effect. Using benzene as a model for the environmental crystal effect,28 the energy difference between A1 and I1 was lowered from 11 to 7 kcal mol−1 (Table S1, Supporting Information). In the more polar environment DMSO the energy difference was reduced further, to only 1 kcal mol−1, and I1 is now even more stable than I2. Thus, the environment stabilizes the I1 conformer more than the A1 and I2 conformers due to its larger dipole moment (μ = 10.0, 6.6, and 5.4 D, respectively). Only small charge changes were observed in the different structures except for the proton position in the I1 and A1 tautomers.

tion). Thus, our crystal structure studies show that in the form II crystal structure of molecule VI, the sulfonimide is the favorable tautomer. Notably, the picture appears quite different if we reduce the crystal to smaller clusters of molecule VI (vide infra). Geometry optimization of sulfonimide and sulfonamide monomers of molecule VI extracted from the two optimized crystal structures clearly showed that molecule VI in its monomeric form is preferably a sulfonamide rather than a sulfonimide, in sharp contrast to that observed in the crystal structure. The calculated energy difference of optimized sulfonimide monomers (I1, Scheme 1) and sulfonamide (A1) Scheme 1. Left, Schematic Representation of Relative Energies of Imide and Amide Monomers and Dimer Tautomers; Right, Equilibra of Different Imide and Amide Monomers and Dimer Tautomers

conformers was found to be 11 kcal mol−1 using M06/631+G(d,p) in favor of the sulfonamide tautomer. To further Table 1. Experimental and Calculated Bond Distances (in Å) model

imide/amide

single-crystal X-ray

imide

Molecule VI UJIRIO Molecule VI UJIRIO05 I1

single-crystal X-ray single-crystal X-ray M06 SCS-MP2 M06-benzene M06-DMSO M06 SCS-MP2 M06-benzene M06-DMSO M06 M06-benzene M06 M06-benzene M06

imide imide imide

A1

(I1)2a (A1)2a Z1a I1-crysta

a

method

molecule VI UJIRIO02

A1-crysta Z1-crysta sulfapyridine18

PBE-D2 PW91(d)10 PBE-D2 PBE-D2 single-crystal X-ray

2-(benzene-sulfonamido)-pyridinium nitrate29

single-crystal X-ray

amide

imide amide zwitterion imide amide zwitterion amide imide zwitterion

Δ(C−N)

N8···H

O10···H

C6−N7

1.376 1.376 1.357 1.377 1.393 1.383 1.387 1.381 1.333 1.335 1.332 1.337 1.377 1.379 1.338 1.339 1.359

C2−N1

1.373 1.379 1.355 1.364 1.315 1.314 1.328 1.355 1.409 1.419 1.425 1.442 1.348 1.353 1.412 1.416 1.382

C2−N8

0.003 −0.003 0.002 0.013 0.078 0.069 0.059 0.026 −0.076 −0.084 −0.093 −0.105 0.029 0.026 −0.074 −0.077 −0.023

2.029 2.068 2.353 2.283

1.947 1.866 1.911 2.008

1.346 1.341 1.331 1.333 1.371

1.379 1.378 1.348 1.363 1.343(4) 1.352(4) 1.349(2)

1.368 1.367 1.411 1.392 1.409(4) 1.361(3) 1.378(2)

0.011 0.011 −0.063 −0.029 −0.065 −0.009 −0.039

1.374

1.921 2.013 2.001 2.025 1.706

1.836 1.857 1.926 1.965 1.887

1.894 1.913 1.841 1.668

1.764 1.764 1.870 1.784

1.351 1.359 1.340 1.373 1.347

Averaged distances. 3706



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(Scheme 2). The M06 calculated energy barrier for the initial proton transfer was found to be 10.1 kcal mol−1. To return

Some of the structural differences between the sulfonimide and the sulfonamide are obviously the C2−N8 and C2−N1 bonds (Table 1). In the M06 optimized structure of sulfonimide I1, the C2−N8 bond is short and the C2−N1 bond is long, while in the sulfonamide A1 the opposite is found. In the X-ray crystal structure II of VI, these bonds are more equal (1.373−1.379 Å), thus indicating a core ring structure with bond lengths in between those found in the sulfonimide and sulfonamide monomers. The solid-state DFT optimized structures I1-cryst and A1-cryst feature bonds with lengths of 1.368 and 1.379 Å and 1.411 and 1.348 Å, respectively (Table 1). It is interesting to compare the A1-cryst structure parameters with the sulfonamide crystal structure from sulfapyridine. As seen in Table 1, the agreement in bond lengths is gratifyingly very good, which clearly validates A1cryst as a viable crystal structure and apparently that our DFT calculations are in fine agreement with experiments. This is further evidenced comparing the I1-cryst bond lengths, which are very close to those calculated by Chan and co-workers10 (Table 1). Another interesting point is the C6−N7 distance, which both in the experimental and predicted crystal structures is shorter (1.33−1.35 Å) than in the monomers A1 and I1 (1.37 Å). This is likely due to the strong hydrogen bonds between the amine group and the oxygens and/or sulfonimide nitrogen observed in the crystal structures, giving the C6−N7 bond more double bond character and thus shorter distance. This is captured already in the dimer models (A1)2 and (I1)2 where a bond shortening is partially experienced (1.35−1.36 Å) due to hydrogen bonding. However, two things that are not understood at this point are, first, why the bond lengths in the I1 monomer and in the X-ray structure differ that much, and second, why the C2−N bond lengths in the X-ray structure are more equal. We hypothesized four different reasons for the deviation between experiment and theory: (a) M06 does not adequately reproduce the geometries of I1 and A1. (b) The environment has a large structural effect. (c) The experimental structure represents two structures rapidly interconverting via a fast intermolecular solid-state proton transfer not resolved by X-ray diffraction. (d) The specific hydrogen bonds in the crystal structure have a large structural effect on the C−N bonds. We addressed these options as follows: (a) Geometry optimization of I1 and A1 using SCS-MP2/ def2-TZVP resulted in C−N bond lengths very similar to those optimized with M06 (Table 1) indicating that the DFT method gives reliable geometries. (b) The polarization effect was analyzed by optimizing the monomers both in benzene and in DMSO, and we found that the C−N bond length differences Δ increased for A1 but decreased for I1 (Table 1). Thus, the environment has a structural effect making the bond lengths for I1 closer to the experimental crystal structure values. We saw earlier that the crystal environment also stabilizes the I1 structure better than A1. (c) To investigate the possible rapid proton transfer, we optimized dimers constructed from the sulfonimide and sulfonamide optimized crystal structures, respectively, and located transition states for proton transfers. An interesting observation is that a direct path where the two protons are transferred synchronously could not be located, although many attempts were made. Instead, we found this to be a two-step transfer mechanism via a zwitterionic dimer intermediate (Z1), which is 9.7 kcal mol−1 less stable than the (I1)2 dimer

Scheme 2. M06/6-31+G(d,p) and SCS-MP2/def2-TZVP// M06 (Italic) Calculated Energies (in kcal mol−1) for Proton Transfer from Sulfonimide Dimer (I1)2 to Sulfonamide Dimer (A1)2 via Zwitterionic Intermediate Z1

from Z1 to the sulfonamide dimer (A1)2, a second TS on this shallow part of the energy surface needs to be passed, with a barrier of 10.9 kcal mol−1. The bulk environment effect on the barrier was found to be modest (11.7 kcal mol−1). Using SCSMP2//M06, we found the first TS to be slightly higher in energy than the second, but the overall barrier for equilibration was found to be 11.7 kcal mol−1, in fine agreement with the M06 results. These values show that the proton transfer indeed is a fast process. This is similar to observations of fast proton transfer in the solid-state of a bicyclic guanidine, where a barrier of ca. 11 kcal mol−1 was reported.30 For Z1, we found each unit to bear ca. 0.75 units of charge indicating a high degree of charge localization. The reaction energy is found to be almost zero at the M06 level of theory, but inclusion of polarization effects makes (I1)2 more stable than (A1)2 (2.2 kcal mol−1 in benzene and 4.4 kcal mol−1 in DMSO). However, the reaction energy was found to be sensitive to the computational method used, and we found a variation from being endothermic (+2.6 using PBE-D2) to exothermic (−7.1 kcal mol−1 using MP2), and from these results, we can not finally conclude if (I1)2 or (A1)2 is the most stable dimer. Most importantly, we see that going from monomer via the dimer and finally to the crystal the relative energies between sulfonamide and sulfonimide changes from largely positive to largely negative. One parameter that we found useful to compare is the difference in dimerization energy for the tautomers I1 and A1. All our computational methods suggest that I1 outperforms A1 in stabilizing a dimer structure, by as much as 12−16 kcal mol−1 (Scheme 1 and Table S1, Supporting Information). Also, the polarization effect was found to stabilize the (I1)2 dimer better than the (A1)2 dimer (vide supra). So even though the sulfonamide monomer A1 is as much as 11 kcal mol−1 more stable than I1 in the gas phase, the structural findings presented above and the calculated energies indicate that the crystal 3707



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barrier proton transfers could be a general phenomenon for sulfonamides. (d) What are the key interactions in the crystal structure that compensate for as large energy difference as 11 kcal mol−1? In the sulfonimide dimer the C−N distances are more equalized compared to that in the monomer, while there is almost no effect for the sulfonamide dimer. This indicates that the dimerization via hydrogen bonding causes a structural change in the C−N bond lengths in (I1)2. Still, the distances in (I1)2 are different from those observed in the crystal structure. Optimization of the dimers in benzene shows similar trends as for the monomers, making the sulfonimide in closer agreement with experiments, but the bond length changes are much smaller than seen for the monomer. In DMSO, the sulfonimide hydrogen bond pattern is significantly changed from that observed in the crystal structure of form II, indicating overestimation of the polarity in the molecular crystal of VI and that benzene is a better model (Table S2, Supporting Information). In the gas phase it is observed that the N−H hydrogen bonds in (I1)2 are shorter and stronger than those in (A1)2 (Table 1). Also the hydrogen bond between the sulfoxide oxygen and amine proton is shorter in (I1)2 than that in (A1)2. In addition, the hydrogen bonds in (I1)2 are more linear (∼175°) than in (A1)2 (165°) making the orbital interactions more favorable. Optimization in benzene, however, increases the N−H hydrogen bond distances in both dimers, making them almost equal, while the O−H hydrogen bond distances are more different than in the gas phase. Thus, the environmental ef fects that favor I1, together with some stronger hydrogen bonds, are the key factors driving the equilibrium toward the (I1)2 synthon formation (Scheme 1) and f rom there on f urther crystallization. To further evaluate the bonding patterns in the tautomeric dimers we created noncovalent interaction (NCI) plots (Figure 5).32 From these plots one can visualize hydrogen bonds and dispersion interactions.33 The color coding interpretation of the isosurfaces (IS) indicate that the hydrogen bonds are somewhat stronger in the (I1)2 dimer than those in the (A1)2 dimer, while the partial overlap between the phenyl rings is slightly larger in the relaxed (A1)2 dimer. As a comparison, the strong intermolecular hydrogen bonds in the zwitterionic dimer are

structure of VI is not constructed of sulfonamide tautomers. After successfully identifying the zwitterion intermediate Z1 we optimized a polymorph crystal structure (Z1-cryst) consisting of such a dimer core. However, this was found to be 5.0 kcal mol−1 less stable than the sulfonimide crystal structure, thus with similar stability as the sulfonamide crystal structure using PBE-D2. Similarly, at the B3LYP-D2 level of theory the relative energy of the crystal structure of Z1 is +6.3 kcal mol−1. The bond lengths in Z1-cryst are similar to those found in 2(benzenesulfonamido)-pyridinium nitrate,29 thus being protonated at both nitrogens, showing its intermediate imide/amide character. Only a few examples of stable zwitterionic crystals constructed of the same molecule have been found in the literature.30,31 From Scheme 2 it is seen that the relative energy of Z1 is a good estimate for the proton transfer barrier also in the crystal structure. Thus, the low barrier for proton transfer allows us to speculate that in the crystal structure of VI there could be unresolved dynamical effects due to rapidly interconverting structures rather than a static structure. Further evidence for this will require more detailed experimental temperature X-ray studies, which is beyond the scope of this article. However, in the study by Gelbrich and co-workers on sulfapyridine where both tautomers were present in the same crystal structure, the sulfonamide protons show a rather large thermal fluctuation even at the temperature of 120 K, which could be indicative of dynamical effects.18 To further investigate this and to ensure that our low calculated barrier is not unique for molecule VI, we also calculated the relative energies of three dimer analogues of Z1 and (I1)2 found in the CCDC database (Figure 4). For all these systems, the relative energies of the

Figure 4. Analogues of VI.

zwitterions are within 7.3−10.2 kcal mol−1, in comparison with 9.7 kcal mol−1 for the parent molecule VI indicating that low

Figure 5. Noncovalent interaction plots of sulfonimide (left), sulfonamide (middle), and zwitterionic (right) dimers. Reduced density gradient isosurface (IS) cutoff set to 0.25. Red IS = unfavorable interaction; green IS = weak favorable interaction; blue IS = strong favorable interaction. 3708



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also given in Figure 5. Moreover, we observe a shorter distance between the two tautomeric NH protons in the sulfonamide dimer than in the sulfonimide. For example, in the dimer models, these are 2.36 and 2.54 Å apart, respectively. This has two effects; it gives a stronger Coulomb repulsion in the sulfonamides, but on the contrary, the stabilizing dispersion effects are also stronger, as seen in Figure 5. The exact relation between the magnitudes of these interactions has not been further investigated. Similar discussions regarding hydrogenbond donor (D) and hydrogen-bond acceptor (A) patterns, such as AADD (for example, sulfonimide dimer) and ADAD (for example, sulfonamide dimer) and its general crystal structure preference can be found, for example, in work by Meijer and co-workers34 or Lüning and co-workers.35

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CONCLUSIONS In summary, we have investigated the inherent structure of molecule VI and found a large energetic preference (11 kcal mol−1) for the monomer to exist as a sulfonamide tautomer. Polarization effects and stronger hydrogen bonds, however, remarkably shift the equilibrium toward sulfonimide tautomers both in dimer clusters and in the crystal structure. Predicted polymorphs of tautomeric forms of VI such as the sulfonamide tautomer crystal structure A1-cryst and the zwitterionic tautomer crystal structure Z1-cryst have been computationally analyzed. Both of these are ca. 5 kcal mol−1 less stable than the sulfonimide tautomer crystal structure I1-cryst. The estimated barrier for proton transfers within the crystal structure is as low as 6−10 kcal mol−1, indicating a rapid process.

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ASSOCIATED CONTENT

S Supporting Information *

Figures, Cartesian coordinates, and energies of structures, CSP of polymorphs of A1-cryst, and tables with detailed energies and structures using different computational methods. This material is available free of charge via the Internet at http:// pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*(S.O.N.L.) E-mail: [email protected]. Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes

The authors declare no competing financial interest.

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REFERENCES

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Sulfonimide or Sulfonamide? - American Chemical Society

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