Molecular Complexes of Alprazolam with Carboxylic Acids, Boric Acid, Boronic Acids, and Phenols. Evaluation of Supramolecular Heterosynthons Mediated by a Triazole Ring✩✩Additional Supporting Information may be found in the online version of this article.

Varughese, Sunil; Azim, Yasser; Desiraju, Gautam R.

doi:10.1002/jps.22117

Cited by 38 publications

(20 citation statements)

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“…Alprazolam is marketed under the trade names Xanax, Xanor, Alprax, and Niravam and these are among the most marketed drugs in the United States and Europe. In the present paper we discuss the recognition patterns in the co-crystals of alprazolam with 4-carboxy phenylboronic acid (CPBA), 4-methoxyphenylboronic acid (4MPBA), 3-methoxyphenylboronic acid (3MPBA) and 2,5-thiophenebisboronic acid (TBA) in addition to molecular complexes with 1,4-benzene-diboronic acid (BDBA) and 4-hydroxyphenylboronic acid (HPBA), which was mentioned in our earlier report [30].…”

Section: Co-crystals With Alprazolammentioning

confidence: 95%

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Phenylboronic acids in crystal engineering: Utility of the energetically unfavorable syn,syn-conformation in co-crystal design

2011

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Phenylboronic acids can exist, in principle, in three different conformers (syn,syn; syn,anti and anti,anti) with distinct energy profiles. In their native state, these compounds prefer the energetically favored syn,anti-conformation. In molecular complexes, however, the functionality exhibits conformational diversity. In this paper we report a series of co-crystals, with N-donor compounds, prepared by a design strategy involving the synthons based on the syn,syn-conformation of the boronic acid functionality. For this purpose, we employed compounds with the 1,2-diazo fragment (alprazolam, 1H-tetrazole, acetazolamide and benzotriazole), 1,10-phenanthroline and 2,2'-bipyridine for the co-crystallization experiments. However, our study shows that the mere presence of the 1,2-diazo fragment in the coformer does not guarantee the successful formation of co-crystals with a syn,syn-conformation of the boronic acid.Typical cyclic OH···N hydrogen bonds formed by boronic acids with alprazolam (a) and 1,10-phenanthroline (b).The -B(OH) 2 fragment makes unsymmetrical O-H···N heterosynthons with alprazolam (ALP) and 1,10-phenanthroline (PHEN). In the co-crystals of phenylboronic acids with 1H-tetrazole (TETR) and 2,2'-bipyridine (BPY), the symmetrical boronic acid dimer is the major synthon. In the BPY complex, boronic acid forms linear chains and the pyridine compound interacts with the lateral OH of boronic acid dimers that acts as a connector, thus forming a ladder structure. In the TETR complex, each heterocycle interacts with three boronic acids. While two boronic acids interact using the phenolic group, the third molecule generates O-H···N hydrogen bonds using the extra OH group, of -B(OH) 2 fragment, left after the dimer formation. Thus, although molecules were selected retrosynthetically with the 1,2-diazo fragment or with nearby hetero-atoms to induce co-crystal formation using the syn,syn-orientation of the -B(OH) 2 functionality, co-crystal formation is in fact selective and is probably driven by energy factors. Acetazolamide (ACET) contains self-complementary functional groups and hence creates stable homosynthons. Phenylboronic acids being weak competitors fail to perturb the homosynthons and hence the components crystallize separately. Therefore, besides the availability of possible hydrogen bond acceptors in the required position and orientation, the ability of the phenyl-boronic acid to perturb the existing interactions is also a prerequisite to form co-crystals. This is illustrated in the 1910 Varughese S, et al. Sci China Chem December (2011) Vol.54 No.12 table below. In the case of ALP, PHEN and BPY, the native structures are stabilized by weak interactions and may be influenced by the boronic acid fragment. Thus phenylboronic acids can attain co-crystals with those compounds, wherein the cyclic O-H···N hydrogen bonds are stronger than the individual homo-interactions. This can lower the lattice energy of the molecular complex as compared with the individual crystals.Heterosynthons formed by boronic a...

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Section: Co-crystals With Alprazolammentioning

confidence: 95%

“…The present study is an extension of our earlier work on the synthon preferences of various functional groups towards a 1,2,4-triazole containing drug-alprazolam (ALP) [30]. This paper reports a series of co-crystals designed using the syn,syn-orientation of the boronic acid by the deliberate choice of N-donor compounds .…”

Section: Introductionmentioning

confidence: 96%

Phenylboronic acids in crystal engineering: Utility of the energetically unfavorable syn,syn-conformation in co-crystal design

2011

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“…Equilibria involving multiple protonation sites and tautomers are not easy to summarize with a single molecular structure, at least without the risk of causing confusion. A single structure with multiple

p K_{a}

values printed next to its atoms, as exemplified by Figure , can rarely adequately represent the order of protonation, the presence of tautomeric forms, the aspects of micro‐ and macro‐

p K_{a}

, and yet one sees such diagrams in the literature, no doubt for the reason of compactness of presentation. There is a single protonation form in Figure , although in reality multiple protonation forms are responsible for the numbers shown (compare to Figure ).…”

Section: Presentation Of Complex Equilibriamentioning

confidence: 99%

Quantum chemical prediction for complex organic molecules

Philipp

Watson

et al. 2017

Int J of Quantum Chemistry

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Numerous types of quantum chemical calculations and protocols have been successfully applied to computing pK a of small, uncomplicated organic molecules. Here, we argue for the need to shift attention to more challenging molecules that are marked by an interplay of complicating factors such as conformational, tautomeric, steric, and other effects. The challenge is not in choosing the right quantum chemical method and solvation model but in combining the existing methods to simultaneously and accurately describe the breadth of chemical and physical phenomena that give rise to the experimentally observed pK a . The complexity of the phenomena that must be considered begs for the need for a greater automation of pK a prediction workflows. We review our experience with these challenges and outline paths for future progress in the direction of tackling pK a prediction of complex organic molecules.complex, pK a , prediction, protonation, quantum | SI M P L E A N D COM P LE X M OL ECU L E SThere is little doubt that methods of pK a prediction based on quantum chemistry and normally employing density functional theory (DFT) energy calculations have largely achieved their goals when it comes to small, simple organic molecules. Such molecules tend to have fewer than 20-30 atoms, are characterized by a single and well-known functional group responsible for the measured pK a , and are relatively rigid. Their predicted pK a values often lie within 0.5 units of the experimental values, the corresponding protocols are uncomplicated and the interpretation of the results straightforward. [1][2][3] To predict the pK a of these compounds is usually not a goal in itself. Their dissociation constants are known from experiment, and in any case can be accurately and instantly predicted by empirical methods. So these small compounds are used mostly in proof-of-principle studies or for method development.The situation with complex organic molecules is very different. Proteins aside, being a separate topic, complex organic molecules, as far as pK a prediction goes, are characterized by one or more of the following features: 50 atoms and more, considerable flexibility with the possibility of forming intramolecular hydrogen bond and other noncovalent interactions, steric effects, several functional groups that might take part in protonation/ deprotonation equilibria (PDE), symmetry-equivalent functional groups, multiple possible tautomeric forms, including zwitterionic species (which might be hard to describe with implicit solvation models), unusual or novel functional groups or heterocycles, and more than one stereocenter that can influence pK a (see Figure 1). An often quoted figure of 1.4 kcal/mol on the energy scale, [4] (which is a small error for DFT energetics), corresponds to 1 unit on the logarithmic scale (which is quite a large error for pK a prediction), so the phenomena aforementioned must either all be described very accurately or a favorable cancelation of errors must be achieved. In view of the multitude of the complicating ...

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“…(Only organic structures with determined three-dimensional coordinates have been analyzed and double entries, as well as disordered structures of DCA and DCP derivatives, have been omitted.) The independent hits (16 for DCP and 15 for DCA) were one solvent-free structure for each of DCP and DCA [DCP: CSD refcode DCLPHL (Bavoux & Michel, 1974); DCA: WEMDEX (Dou et al, 1993) For DCP, ten structures are neutral, of which three display a three-dimensional network [CAKYOE (Varughese et al, 2010), GAKVAP (McKinney & Singh, 1988) and SILGOK (Gonzá lez Martínez & Bernè s, 2007)]. In CAKYOE, a C-HÁ Á ÁCl hydrogen bond supports the three-dimensional network, while O-HÁ Á ÁCl and weak ClÁ Á ÁCl interactions are present in SILGOK.…”

Section: Figure 13mentioning

confidence: 99%

Cocrystals of 2,6-dichloroaniline and 2,6-dichlorophenol plus three new pseudopolymorphs of their coformers

Gerhardt

Bolte

2015

Acta Crystallogr C

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The structures of cocrystals of 2,6-dichlorophenol with 2,4-diamino-6-methyl-1,3,5-triazine, C6H4Cl2O·C4H7N5, (III), and 2,6-dichloroaniline with 2,6-diaminopyrimidin-4(3H)-one and N,N-dimethylacetamide, C6H5Cl2N·C4H6N4O·C4H9NO, (V), plus three new pseudopolymorphs of their coformers, namely 2,4-diamino-6-methyl-1,3,5-triazine-N,N-dimethylacetamide (1/1), C4H7N5·C4H9NO, (I), 2,4-diamino-6-methyl-1,3,5-triazine-N-methylpyrrolidin-2-one (1/1), C4H7N5·C5H9NO, (II), and 6-aminoisocytosine-N-methylpyrrolidin-2-one (1/1), C4H6N4O·C5H9NO, (IV), are reported. Both 2,6-dichlorophenol and 2,6-dichloroaniline are capable of forming definite synthon motifs, which usually lead to either two- or three-dimensional crystal-packing arrangements. Thus, the two isomorphous pseudopolymorphs of 2,4-diamino-6-methyl-1,3,5-triazine, i.e. (I) and (II), form a three-dimensional network, while the N-methylpyrrolidin-2-one solvate of 6-aminoisocytosine, i.e. (IV), displays two-dimensional layers. On the basis of these results, attempts to cocrystallize 2,6-dichlorophenol with 2,4-diamino-6-methyl-1,3,5-triazine, (III), and 2,6-dichloroaniline with 6-aminoisocytosine, (V), yielded two-dimensional networks, whereby in cocrystal (III) the overall structure is a consequence of the interaction between the two compounds. By comparison, cocrystal-solvate (V) is mainly built by 6-aminoisocytosine forming layers, with 2,6-dichloroaniline and the solvent molecules arranged between the layers.

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Molecular Complexes of Alprazolam with Carboxylic Acids, Boric Acid, Boronic Acids, and Phenols. Evaluation of Supramolecular Heterosynthons Mediated by a Triazole Ring✩✩Additional Supporting Information may be found in the online version of this article.

Cited by 38 publications

References 33 publications

Phenylboronic acids in crystal engineering: Utility of the energetically unfavorable syn,syn-conformation in co-crystal design

Phenylboronic acids in crystal engineering: Utility of the energetically unfavorable syn,syn-conformation in co-crystal design

Quantum chemical prediction for complex organic molecules

Cocrystals of 2,6-dichloroaniline and 2,6-dichlorophenol plus three new pseudopolymorphs of their coformers

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