The use of solid-state NMR and X-ray crystallography as complementary tools for studying molecular recognition

Vojta, Gail M.; Etter, Margaret C.

doi:10.1016/0263-7855(89)80052-9

Cited by 19 publications

(4 citation statements)

References 26 publications

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“…Active pharmaceutical ingredients are often conformationally complex molecules, sometimes with significant barriers that limit the kinetics of interconversion between conformers. − A number of studies suggest that the kinetics of crystallization can be affected by the presence of multiple conformers, particularly when the kinetics of conformer interconversion are slow and when the conformer in the crystal is a minority conformer in the solution. − Throughout this paper, we refer to the conformer in the crystal structure as the growth conformer.…”

Section: Introductionmentioning

confidence: 99%

Crystal Growth Impedance from Slow Conformer Interconversion in Bulk Solution

Zadeh

Peters

2022

Crystal Growth & Design

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Small molecules often exhibit multiple metastable conformers in solution while their crystal structures incorporate only one of the conformers. Several studies have hypothesized that slow conformer interconversion could impede the kinetics of crystal growth. This study develops coupled species and population balances to model the kinetics of conformer interconversion and crystal growth in a mixed suspension mixed product removal crystallizer at steady-state. To isolate the effects of slow interconversion, we develop, nondimensionalize, and solve two models. One model includes finite interconversion rates and the other "control" model assumes rapid interconversion such that the conformers are at equilibrium with each other in solution. Finally, we develop and analyze a version of the model in which the incorrect conformer can block sites for attachment of the growth conformer. The models show that slow interconversion causes unequal supersaturations of the two conformers in solution and reduces the total crystal volume fraction in solution, but does not alter the crystal size distribution.

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Section: Introductionmentioning

confidence: 99%

Crystal Growth Impedance from Slow Conformer Interconversion in Bulk Solution

Zadeh

Peters

2022

Crystal Growth & Design

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“…11 Etter and Vojta suggested that solution phase conformers influence polymorphism via their different propensities for incorporation at the crystal surface. 12 Maruyama and Ooshima suggested that conformational similarity between the solution and crystal is favorable for growth rates. 13 Kessler et al studied conformers of Didemnins in DMSO and noted that the solution phase and crystallized conformers were separated by a significant (ca.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Clever experiments by Jaeschke et al showed that a warm-reflux and recooling step can accelerate conformer equilibration in the bulk and accelerate growth rates . Etter and Vojta suggested that solution phase conformers influence polymorphism via their different propensities for incorporation at the crystal surface . Maruyama and Ooshima suggested that conformational similarity between the solution and crystal is favorable for growth rates .…”

Section: Introductionmentioning

confidence: 99%

Conformational Interconversion Kinetics, Boundary Layer Transport, and Crystal Growth Impedance

Zadeh

Peters

2022

Crystal Growth & Design

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Several experiments and computational reports suggest that conformational interconversion kinetics can impede crystal growth. In this work, we model the separate conformer concentrations accounting for their diffusion through the boundary layer, kinetics of conformer interconversion, and kinetics of incorporation at the crystal surface. We solve the equations in terms of dimensionless parameters to reveal when conformational interconversion kinetics will cause depletion of the growth conformer in the boundary layer and how severely this depletion will impede growth. We use the results to assess the impact of conformer interconversion kinetics in several earlier experimental and computational reports.

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“…It is well suited to studies of both ordered and disordered materials, − providing valuable information on short-range order. NMR-enhanced crystallography combines information on the local structure (SSNMR) with details on long-range order (powder X-ray diffraction, PXRD) for elucidating structures of solids. , Although SSNMR has been used to study crystalline or amorphous MOFs and guest inclusion, − there have been relatively few reports of the elucidation of the full structure of MOF using NMR. , Importantly, the role of NMR spectroscopy in structural characterization of new organic or metal–organic materials is typically limited to quantification of the contents of the asymmetric unit, specifically determination of Z ′ (i.e., the number of molecules in the asymmetric unit). − …”

Section: Introductionmentioning

confidence: 99%

NMR-Enhanced Crystallography Aids Open Metal–Organic Framework Discovery Using Solvent-Free Accelerated Aging

et al. 2020

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We demonstrate the combined use of NMR-enhanced crystallography and solvent-free synthesis by accelerated aging (AA), for the discovery and structural characterization of a novel cadmium-based open metal-organic framework belonging to the class of zeolitic imidazolate frameworks (ZIFs). Whereas solid-state NMR spectroscopy has been used to assist in structural characterization of crystalline solids by powder X-ray diffraction (PXRD), typically through quantification of the contents of the asymmetric unit, this work highlights how it can take a more active role in guiding structure determination, by elucidating the coordination environment of the metal node in a novel metal-organic framework. Exploration of AA reactions of cadmium oxide (CdO) and 2-methylimidazole (HMeIm) enabled the synthesis of the previously reported yqt1-topology framework, but also a new material (1) exhibiting a Cd:MeIm ratio of 1:3, contrasting the 1:2 ratio expected for a ZIF. Structural characterization of 1 was enabled by using 111 Cd solid-state nuclear magnetic resonance (SSNMR) to provide information on the coordination environment of the cadmium node. Specifically, 111 Cd SSNMR experiments were conducted on a series of model compounds to correlate the cadmium coordination environment to the observed isotropic chemical shift, δiso( 111 Cd), followed by multinuclear SSNMR experiments on 1 to determine the nature of the metal coordination environment and the number of distinct chemical sites. This information was used in refinement of the molecular-level structure from the available powder X-ray diffraction data, a technique termed NMR-enhanced crystallography, revealing that 1 is an open diamondoid (dia) topology Cd(MeIm)2 framework based on Cd 2+ ions tetrahedrally coordinated with MeImligands, and additional HMeIm guest molecules within the framework pores. Whereas accelerated aging was initially devised as a clean, mild route for making MOFs, these results provide a proof-of-principle of how, by combining it with SSNMR spectroscopy as a means to overcome limitations of PXRD structure determination, it can be used to screen for new solid phases in the absence of solvents, high temperatures or mechanical impact that are inherent to other thermally-, solution-or mechanochemicallybased techniques.

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The use of solid-state NMR and X-ray crystallography as complementary tools for studying molecular recognition

Cited by 19 publications

References 26 publications

Crystal Growth Impedance from Slow Conformer Interconversion in Bulk Solution

Crystal Growth Impedance from Slow Conformer Interconversion in Bulk Solution

Conformational Interconversion Kinetics, Boundary Layer Transport, and Crystal Growth Impedance

NMR-Enhanced Crystallography Aids Open Metal–Organic Framework Discovery Using Solvent-Free Accelerated Aging

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