NMR crystallography of molecular organics
Graphical abstract
Introduction
NMR has been used to obtain crystallographic data from its earliest days, the pioneering example being Pake’s measurement of the distance between the hydrogen atoms of water in gypsum (CaSO4·2H2O) via the dipolar coupling between the 1H nuclei [1]. But despite the natural complementarity between the sensitivity of diffraction and NMR to long-range ordering and short-range environment respectively, the interactions between NMR and diffraction crystallography have traditionally been limited. The identification of crystallography with diffraction studies must have seemed complete with International Union of Crystallography’s (IUCr’s) 1991 re-definition of a crystal as “a material [with an] essentially a sharp diffraction pattern” [2]. Recent years have, however, seen a significant strengthening of interactions between these different ways of characterising solid materials. This is reflected in journal special issues on “NMR crystallography” [3], [4], [5], a dedicated handbook [6], and in 2014, the creation of an IUCr subject grouping (commission) in NMR crystallography [7]. There are also a number of valuable reviews of the area; Bryce’s 2017 article gives a compact and wide-ranging overview [8], while Martineau et al. [9], and Ashbrook and McKay [10] have written comprehensive overviews of NMR crystallography applied to both organic and inorganic materials.
This review focusses on the applications of NMR crystallography to crystals of small molecular organics, often termed “chemical crystallography”. This is a significant narrowing of the field of applications given that a major strength of NMR is its applicability to all sample types, including materials, such as polymers and glasses, that are challenging for diffraction-based methods. It is, however, the area of NMR of small molecule crystals that has seen the most rapid developments, as a result of the development of efficient Density Functional Theory (DFT) codes that allow NMR parameters to be directly correlated to crystal structures. Progress has been particularly rapid for molecular organics, aided by the fact that a relatively limited subset of nuclei (notably 13C and 1H) are sufficient for most problems. While acknowledging notable applications of NMR methods to other material types, we will try to give a comprehensive review of the state-of-the-art for molecular organic solids (up to 2018), focussed in the past decade in which DFT calculations have played an important role. Reviews of other material types with an emphasis on NMR crystallography include articles on crystalline microporous materials [11], nucleic acid components [12], peptides [13], inorganic materials [14], pharmaceutical materials [15], [16], and supramolecular assembly [17]. Ref. [18] and citations within provide excellent illustrations of NMR crystallographic methods applied to complex biomolecules. The focus of the current review is showing how NMR has been used to provide new crystallographic insight, allowing new researchers in the field to understand what crystallographic problems can be realistically tackled via NMR methods, at the expense of excluding papers where the NMR is tangential to the crystallography.
The concept of NMR as a crystallographic tool seems unnatural for most synthetic chemists. Successful crystallisation of a product, and confirmation of its chemical identity via single-crystal X-ray diffraction (SCXRD) typically forms a tidy end-point to a synthesis. In other cases, however, the three-dimensional structure of the material is of direct interest, and characterising the different solid forms available is essential, whether these forms are amenable to single-crystal diffraction or not. This is particularly true in pharmaceutical applications, where the appearance of a previously unknown polymorph can be disastrous; well-known cases include ritonavir [19] and, more recently, rotigotine [20]. In both of these cases, the product had to be withdrawn from the market and reformulated. The importance of complete characterisation of the pharmaceutical solids, beyond single-crystal diffraction studies, is illustrated by a number of edited volumes on the topic [21], [22], [23].
The most obvious limitation of restricting crystallography to SCXRD studies is that many solid forms are not suitable for single-crystal studies. The most obvious examples are amorphous materials, which have no long-range order. Although fully disordered materials are always challenging to characterise, NMR has a particularly useful role to play for disordered materials, as discussed in Section 3.9. In other cases, materials may be locally ordered, but the crystallites may simply be too small for conventional single-crystal XRD. Obvious examples are materials produced via mechano-chemistry, which typically produces fine powders that can only be characterised by powder diffraction. Significant strides have recently been made in using electron diffraction to obtain structures from very small crystals, but this is a challenging technique where the complementary information from NMR has a potentially valuable role. Powder X-ray diffraction (PXRD) is widely used to characterise finely divided crystalline solids. Much like 13C solid-state NMR, PXRD can readily be used as a finger-printing tool to distinguish crystalline forms of molecular organics, but solving structures from PXRD is a considerable challenge, due to the much lower information content of a 1D diffractogram. The application of NMR to assist structure solution from PXRD and electron diffraction data is discussed in Section 3.6.
NMR would seem to have little useful role to play in characterising materials where a structure solution is already available from single-crystal XRD. It is important, however, to be aware of the intrinsic limitations of XRD. Firstly, any disorder disrupts the “inversion” of the diffraction pattern to structure. For example, even small amplitude thermal motion will distort apparent bond lengths (see Section 2.5.1), while the effects of larger amplitude motions need to be modelled, introducing an element of judgement into the fitting of the electron density pattern. Secondly, the weak scattering of X-rays by the single electron of H atoms means that XRD struggles to accurately locate H atoms. The difficulty of locating H atoms confidently is unfortunate given the importance of hydrogen bonding in structural chemistry. This is discussed in detail in Section 3.2. Thirdly, XRD struggles to differentiate isoelectronic, such as OH vs. F vs. CH3, or near-isoelectronic species, e.g. Si vs. Al. These issues are infrequently encountered in molecular systems, but are a severe problem for materials such as aluminosilicates. The latter two limitations of X-ray diffraction can be avoided using neutron diffraction. However, much larger samples are required due to the weaker scattering of neutrons (often precluding single crystal studies), and the scale of facilities required to support neutron diffraction means it is not a panacea for the limitations of X-ray diffraction.
The bulk of the review is divided into two sections, the first dealing with the methodology of NMR crystallography, while the second reviews the applications of the method. Readers who are primarily interested in what has been achieved with NMR crystallography can skip over the methodology, hopefully to return having been convinced of the opportunities provided by combining NMR and traditional crystallography!
Section snippets
The tools of NMR crystallography
The basic principles of solid-state NMR have been set out in a number of introductory texts [24], [25] and will not be described here. Instead this section reviews the different NMR interactions and the contribution that they can make to crystallographic studies.
Applications of NMR crystallography
This larger part of the review considers different topics in NMR crystallography, giving a critical assessment of the state of the art in the different areas. The first topic considered is that of assignment of the NMR spectrum. Although assignment does not itself provide new crystallographic information, some degree of assignment is an essential first step, and the advent of reliable DFT calculations for periodic systems has had a considerable impact in this area. Moving to more direct
Looking forward
Solid-state NMR has often been seen as a technique of last resort, to be attempted if a material is sufficiently disordered or heterogeneous for characterisation by diffraction methods. The developments in methodology discussed above, coupled with growing use of solid-state NMR as a mainstream characterisation technique, have transformed this situation. It remains the case, however, that NMR is most widely applied for those problems where X-ray diffraction struggles. For example, an array of
Declaration of Competing Interest
The author declares no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
Comments on draft sections of this manuscript from Martin Dračínský (IOCB Prague) and Jonathan Yates (Oxford University) are gratefully acknowledged, as well as the generosity of many colleagues in providing original artwork for many of the figures. This review also greatly benefited from discussions enabled by the Collaborative Computing Project for NMR Crystallography (www.ccpnc.ac.uk), which is funded by the Engineering and Physical Sciences Research Council (grant numbers EP/J010510/1 and
Glossary
- ADP
- Atomic Displacement Parameter(s)
- API
- Active Pharmaceutical Ingredient
- APT
- Attached Proton Test
- CIF
- Crystallographic Information File
- CP
- Cross-Polarisation
- CSA
- Chemical Shift Anisotropy
- CSD
- Cambridge Structural Database
- CSP
- Crystal Structure Prediction
- dc-DFT
- dispersion-corrected DFT
- DFT
- Density Functional Theory
- DNP
- Dynamic Nuclear Polarisation
- DQ
- Double Quantum
- ED
- Electron Diffraction
- FSLG
- Frequency-Switched Lee-Goldburg
- GGA
- Generalised Gradient Approximation
- GIPAW
- Gauge-Including Projector-Augmented Waves
- GTO
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