Diazole-based powdered cocrystal featuring a helical hydrogen-bonded network: Structure determination from PXRD, solid-state NMR and computer modeling

Abstract

We present the structure of a new equimolar 1:1 cocrystal formed by 3,5-dimethyl-1H-pyrazole (dmpz) and 4,5-dimethyl-1H-imidazole (dmim), determined by means of powder X-ray diffraction data combined with solid-state NMR that provided insight into topological details of hydrogen bonding connectivities and weak interactions such as C-H•••π contacts. The use of various 1D/2D 13 C, 15 N and 1 H high-resolution solid-state NMR techniques provided structural insight on local length scales revealing internuclear proximities and relative orientations between the dmim and dmpz molecular building blocks of the studied cocrystal. Molecular modeling and DFT calculations were also employed to generate meaningful structures. DFT refinement was able to decrease the figure of merit R(F 2) from ~11% (PXRD only) to 5.4%. An attempt was made to rationalize the role of N-H•••N and C-H•••π contacts in stabilizing the reported cocrystal. For this purpose four imidazole derivatives with distinct placement of methyl substituents were reacted with dmpz to understand the effect of methylation in blocking or enabling certain intermolecular contacts. Only one imidazole derivative (dmim) was able to incorporate into the dmpz trimeric motif thus resulting in a cocrystal, which contains both hydrophobic (methyl groups) and hydrophilic components that self-assemble to form an atypical 1D network of helicoidal hydrogen bonded pattern, featuring structural similarities with alpha-helix arrangements in proteins. The 1:1 dmpz•••dmim compound I is the first example of a cocrystal formed by two different azoles.

Benchmark fragment-based1H,13C,15N and17O chemical shift predictions in molecular crystals

“…Conversions to other chemical shift scales can be accomplished as described by Ref 37; for expediency, several of the most common conversions are given in the ESI. † The CSD reference codes and experimental references for NMR data for the three test sets are: Hydrogen (13 structures, 80 shifts): CIMETD, 1 INDMET, 38 URACIL, 39 co-crystal of 4,5-Dimethylimidazole and 3,5-Dimethylpyrazole, 40 AMBACO05, 41 PHBARB06, 42 IPMEPL, 7 COYRUD11, 43 FPAMCA11, 8 BAPLOT01, 8 WEZCOT, 8 FLUBIP, 44 ZIVKAQ. 45 …”

Resolving alternative organic crystal structures using density functional theory and NMR chemical shifts

“…Overall this approach of structure distinction via solid-state NMR is not burdensome, since the initial step of structural relaxation using periodic DFT is now well established. Such structural relaxation is particularly valuable where structures have been derived from powder diffraction, either as part of the renement process, 30,31 or, for example, to conrm the validity of structures which are potentially suspect as suggested by high R factors. 32 Measurement of 13 C and 1 H NMR chemical shis is only needed in the relatively small number of cases where the structural relaxation results in different local minima, and where the differences are structurally signicant, Fig.…”

A theoretical NMR study of polymorphism in crystal structures of azoles and benzazoles

“…This work shows the limitations of the combined use of solid-state NMR (SSNMR) and GIPAW calculations to clarify problems related to tautomerism, polymorphism, and desmotropy. [7][8][9][52][53][54][55] When the molecule bears a heavy-atom substituent, either an empirical model using a dummy variable or ZORA-SO calculations are necessary to account for the experimental chemical shifts, especially for atoms directly bonded to an heavy atom, such as bromine and iodine.…”

“…The application of SSNMR as a tool for polymorphism investigation was highlighted on a seminal paper published by Robin K. Harris entitled "Applications of solid-state NMR to pharmaceutical polymorphism and related matters." [7] We have used this approach recently [8] and so have done several authors, for instance, to explore the dynamics of diethylcarbamazine citrate. [9] Recently, we have reported a theoretical NMR study of a set of benzazole crystal structures by using GIPAW calculations.…”