Recurrence of carboxylic acid-pyridine supramolecular synthon in the crystal structures of some pyrazinecarboxylic acids.
TL;DR: X-ray crystal structures of pyrazinic acid 1 and isomeric methylpyrazine carboxylic acids 2-4 are analyzed to examine the occurrence of car boxylic acid-pyridine supramolecular synthon V in these heterocyclic acids.
Abstract: X-ray crystal structures of pyrazinic acid 1 and isomeric methylpyrazine carboxylic acids 2-4 are analyzed to examine the occurrence of carboxylic acid-pyridine supramolecular synthon V in these heterocyclic acids. Synthon V, assembled by (carboxyl)O-H...N(pyridine) and (pyridine)C-H...O(carbonyl) hydrogen bonds, controls self-assembly in the crystal structures of pyridine and pyrazine monocarboxylic acids. The recurrence of acid-pyridine heterodimer V compared to the more common acid-acid homodimer I in the crystal structures of pyridine and pyrazine monocarboxylic acids is explained by energy computations in the RHF 6-31G* basis set. Both the O-H.N and the C-H...O hydrogen bonds in synthon V result from activated acidic donor and basic acceptor atoms in 1-4. Pyrazine 2,3- and 2,5-dicarboxylic acids 10 and 11 crystallize as dihydrates with a (carboxyl)O-H...O(water) hydrogen bond in synthon VII, a recurring pattern in the diacid structures. In summary, the carboxylic acid group forms an O-H...N hydrogen bond in pyrazine monocarboxylic acids and an O-H...O hydrogen bond in pyrazine dicarboxylic acids. This structural analysis correlates molecular features with supramolecular synthons in pyridine and pyrazine carboxylic acids for future crystal engineering strategies.
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TL;DR: This review addresses how crystal engineering has been applied to active pharmaceutical ingredients, API's, with emphasis upon how pharmaceutical co-crystals, a long known but little explored alternative to the four traditionally known forms of API, can be generated in a rational fashion.
904 citations
TL;DR: In this article, the authors provide an overview of some modular and transferable strategies for the synthesis of binary and ternary supermolecules and co-crystals based upon a hierarchy of intermolecular interactions, notably hydrogen bonds.
Abstract: Molecular recognition is typically associated with molecules in solution, but such events are also responsible for organizing molecules in the solid state. Translating principles of molecular recognition to solid-state assembly of heteromeric molecular solids is of key importance to the development of versatile, reliable and practical supramolecular synthesis. In this article we provide an overview of some modular and transferable strategies for the synthesis of binary and ternary supermolecules and co-crystals based upon a hierarchy of intermolecular interactions, notably hydrogen bonds.
672 citations
TL;DR: It has become clear that a wide array of multiple component pharmaceutical phases, so called pharmaceutical co-crystals, can be rationally designed using crystal engineering, and the strategy affords new intellectual property and enhanced properties for pharmaceutical substances.
403 citations
TL;DR: In this paper, the authors evaluate the hierarchy of supramolecular heterosynthons that involve two of the most relevant functional groups in the context of active pharmaceutical ingredients, carboxylic acids and alcohols, in competitive environments.
Abstract: A Cambridge Structural Database (CSD) analysis was conducted in order to evaluate the hierarchy of supramolecular heterosynthons that involve two of the most relevant functional groups in the context of active pharmaceutical ingredients, carboxylic acids and alcohols, in competitive environments. The study revealed that 34% of the 5690 molecular carboxylic acid entries and 26% of the 25 035 molecular alcohol entries form supramolecular homosynthons, whereas the remaining entries form supramolecular heterosynthons with other functional groups, in particular Narom, CONH2, C−O−C, C═O, and chloride anions. Further refinement of this raw data revealed the following: 98% occurrence of the COOH···Narom supramolecular heterosynthon in the 126 crystal structures that contain acid and pyridine moieties in the absence of other hydrogen bond donors or acceptors; and 78% occurrence of the OH···Narom supramolecular heterosynthon in 228 crystal structures that contain hydroxyl and pyridine moieties (excluding intramolec...
402 citations
TL;DR: In this paper, a modular expansion of carboxylic acid dimer in neutral cocrystals with pyridine type bases is shown, which results in a ternary cocrystal 12 sustained via O−H⋯N and O−O− hydrogen bonds, and the length of bipyridinium cation plays a role in the overall structure.
Abstract: Linear, zigzag tapes and flat, corrugated sheet structures are described in binary cocrystals 1–9 of some di- and tricarboxylic acids with 4,4′-bipyridine bases and isonicotinamide. Carboxylic acid⋯pyridine O–H⋯N, its proton transfer form N+–H⋯O−, carboxamide dimer N–H⋯O, and extended motifs are present in these crystal structures. Our results show modular expansion of carboxylic acid dimer in neutral cocrystals with pyridine type bases. Even as the structures of these aggregates can be understood from the molecular constituents in a straightforward manner, the nature of acid⋯pyridine synthon, i.e. neutral or ionic, is difficult to anticipate from their ΔpKa values. We modify the ΔpKa
(pKa conjugate acid of pyridine base – pKa carboxylic acid) rule in COOH–pyridine cocrystals: ΔpKa 3.75 results in proton migration to the ionic interaction N+–H⋯O−. Proton transfer results in the assembly of a supramolecular 3-connected node of cyclohexane tricarboxylate and these anions form chair cyclohexane or parquet grid sheets in 10 and 11. The length of bipyridinium cation plays a role in the overall structure. A novel approach to three-component adducts is crystallization of 1,3cis,5cis-cyclohexane tricarboxylic acid with 4,4′-bipyridine and 4,4′-bipyridine-N-oxide bases of different strengths, which results in a ternary cocrystal 12 sustained via O–H⋯N and O–H⋯O− hydrogen bonds.
355 citations
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TL;DR: In this article, the authors show that crystal engineering is a new organic synthesis, and that rather than being only nominally relevant to organic chemistry, this subject is well within the mainstream, being surprisingly similar to traditional organic synthesis in concept.
Abstract: A crystal of an organic compound is the ultimate supermolecule, and its assembly, governed by chemical and geometrical factors, from individual molecules is the perfect example of solid-state molecular recognition. Implicit in the supramolecular description of a crystal structure is the fact that molecules in a crystal are held together by noncovalent interactions. The need for rational approaches towards solid-state structures of fundamental and practical importance has led to the emergence of crystal engineering, which seeks to understand intermolecular interactions and recognition phenomena in the context of crystal packing. The aim of crystal engineering is to establish reliable connections between molecular and supramolecular structure on the basis of intermolecular interactions. Ideally one would like to identify substructural units in a target supermolecule that can be assembled from logically chosen precursor molecules. Indeed, crystal engineering is a new organic synthesis, and the aim of this article is to show that rather than being only nominally relevant to organic chemistry, this subject is well within the mainstream, being surprisingly similar to traditional organic synthesis in concept. The details vary because one is dealing here with intermolecular interactions rather than with covalent bonds; so this article is divided into two parts. The first is concerned with strategy, highlighting the conceptual relationship between crystal engineering and organic synthesis and introduces the term supramolecular synthon. The second part emphasizes methodology, that is, the chemical and geometrical properties of specific intermolecular interactions.
4,237 citations
TL;DR: Noncovalent synthesis based on the reversible formation of multiple hydrogen bonds is described and the development of novel materials (nanotubes, liquid crystals, polymers, etc.) and principles that recently have emanated from this intriguing field of research are summarized.
Abstract: Hydrogen bonds are like human beings in the sense that they exhibit typical grouplike behavior. As an individual they are feeble, easy to break, and sometimes hard to detect. However, when acting together they become much stronger and lean on each other. This phenomenon, which in scientific terms is called cooperativity, is based on the fact that 1+1 is more than 2. By using this principle, chemists have developed a wide variety of chemically stable structures that are based on the reversible formation of multiple hydrogen bonds. More than 20 years of fundamental studies on these phenomena have gradually developed into a new discipline within the field of organic synthesis, and is nowadays called noncovalent synthesis. This review describes noncovalent synthesis based on the reversible formation of multiple hydrogen bonds. Starting with a thorough description of what the hydrogen bond really is, it guides the reader through a variety of bimolecular and higher order assemblies and exemplifies the general principles that determine their stability. Special focus is given to reversible capsules based on hydrogen-bonding interactions that exhibit interesting encapsulation phenomena. Furthermore, the role of hydrogen-bond formation in self-replicating processes is actively discussed, and finally the review briefly summarizes the development of novel materials (nanotubes, liquid crystals, polymers, etc.) and principles (dynamic libraries) that recently have emanated from this intriguing field of research.
1,060 citations
TL;DR: A molecule is usually understood to be a stable collection of atoms connected by a continuous network of covalent bonds as discussed by the authors, and the develipment of methods for constructing these networks has been a central occupation of organic chemistry, and the success of these methods has made possible the power, elegance and utility of modern organic synthesis.
Abstract: A molecule is usually understood to be a stable collection of atoms connected bv a continuous network of covalent bonds. The develipment of methods for constructing these networks has been a central occupation of organic chemistry, and the success of these methods has made possible the power, elegance, and utility of modern organic synthesis. The preparations of vitamin B12,l palytoxin,2 calicheamicin,3 and other complex secondary metabolites illustrate the extraordinary sophistication of this field. This type of synthesis-which we refer to as covalent synthesis, in the absence of a better termcontinues to expand its capabilities, but it may be understandably difficult to provide very large and structurally complex molecules quickly and economically by using it.4 Organic chemistry has always taken much of its inspiration and motivation from Nature. As biological molecules-especially large molecules having complex tertiary structures such as proteins, DNA, and RNA-have become central concerns of organic chemistry, noncovalent interactions have moved toward the center of attention. Although biological macromolecules are largely composed of Covalent bonds, the networks of these bonds are not always continuous, and many important structures-including multimeric proteins and DNA itself-are "aggregates" and not simply "molecules". Many biological molecules and aggregates derive much of their unique structure and function from noncovalent interactions: that is, from
924 citations
796 citations
TL;DR: The application of self-assembly to the solid state offers an approach to crystal design and crystal engineering, namely supramolecular synthesis of solids, that is based upon the design of infinite networks.
727 citations