New in situ solid-state NMR techniques for probing the evolution of crystallization processes: pre-nucleation, nucleation and growth

Abstract

The application of in situ techniques for investigating crystallization processes promises to yield significant new insights into fundamental aspects of crystallization science. With this motivation, we recently developed a new in situ solid-state NMR technique that exploits the ability of NMR to selectively detect the solid phase in heterogeneous solid-liquid systems (of the type that exist during crystallization from solution), with the liquid phase "invisible" to the measurement. As a consequence, the technique allows the first solid particles produced during crystallization to be observed and identified, and allows the evolution of different solid phases (e.g., polymorphs) present during the crystallization process to be monitored as a function of time. This in situ solid-state NMR strategy has been demonstrated to be a powerful approach for establishing the sequence of solid phases produced during crystallization and for the discovery of new polymorphs. The most recent advance of the in situ NMR methodology has been the development of a strategy (named "CLASSIC NMR") that allows both solid-state NMR and liquid-state NMR spectra to be measured (essentially simultaneously) during the crystallization process, yielding information on the complementary changes that occur in both the solid and liquid phases as a function of time. In this article, we present new results that highlight the application of our in situ NMR techniques to successfully unravel different aspects of crystallization processes, focusing on: (i) the application of a CLASSIC NMR approach to monitor competitive inclusion processes in solid urea inclusion compounds, (ii) exploiting liquid-state NMR to gain insights into co-crystal formation between benzoic acid and pentafluorobenzoic acid, and (iii) applications of in situ solid-state NMR for the discovery of new solid forms of trimethylphosphine oxide and L-phenylalanine. Finally, the article discusses a number of important fundamental issues relating to practical aspects, the interpretation of results and the future scope of these techniques, including: (i) an assessment of the smallest size of solid particle that can be detected in in situ solid-state NMR studies of crystallization, (ii) an appraisal of whether the rapid sample spinning required by the NMR measurement technique may actually influence or perturb the crystallization behaviour, and (iii) a discussion of factors that influence the sensitivity and time-resolution of in situ solid-state NMR experiments.

New in situ solid-state NMR strategies for exploring materials formation and adsorption processes: prospects in heterogenous catalysis

“…In recent years, we have developed [20][21][22][23][24][25] new in situ solid-state NMR strategies for mapping the evolution of the solid phase during the process of materials formation from solution. While we have so far applied this technique primarily (although not exclusively) to study crystallization of organic materials from solution, the technique could equally be applied to study the formation of solids of direct relevance within the domain of heterogenous catalysis (for example, metal-organic-framework materials, zeolites, and aluminophosphates), provided two important criteria are satisfied: (a) the temperature of the process must be within the accessible range for solid-state NMR instrumentation (for which the typical upper limit is ca.…”

“…Importantly, the in situ solid-state NMR technique [20] that we have developed for studying the time evolution of materials formation processes exploits the ability of NMR to selectively detect the solid phase in the types of heterogeneous solid/liquid system that exist during crystallization from solution, with the liquid phase ''invisible'' to the measurement. This technique has been shown to be a powerful approach for establishing the sequence of solid phases produced during crystallization [21][22][23] and for the discovery of new (transient) solid forms [24].…”

“…A number of factors are important in this regard, including: (a) the NMR receptivity of the selected nucleus, (b) the applied magnetic field strength, (c) the NMR relaxation properties, and (d) the total amount of material used in the experiment. In the case of crystallization of organic materials from solution, a more detailed discussion of these issues has been given elsewhere [23]. In general terms, the feasibility of monitoring a particular process using in situ NMR techniques depends on specific details of the process and specific details of the NMR measurement technique to be used.…”

Size‐Control by Anion Templating in Mechanochemical Synthesis of Hemicucurbiturils in the Solid State

“…Incomplete conversion of oligomers into cycHC[n] in the NMR rotor,which contrasts quantitative conversion in sealed vials,c ould be due to inhomogeneous distribution of the material in the rotor during high-speed spinning (3000 s À1 ). [23] In summary,weshow that mechanochemical assembly of six-and eight-membered hemicucurbituril macrocycles can be achieved selectively and quantitatively using either HCl or HClO 4 ,respectively,asadditives,providing the first example of template-directed covalent solid-state synthesis of macrocycles.W hile milling of reactants leads to the formation of solid mixtures of oligomers,u pon aging with as uitable template these powders spontaneously and quantitatively convert into aparticular macrocycle dictated by the choice of acid additive.I ns olution, the macrocyclization reaction equilibrium is known to proceed through DCC,g overned by the formation of an anion inclusion complex [10b] which appears to be unfavored under mechanochemical conditions, but becomes prevalent in aging. To the best of our knowledge, the herein demonstrated spontaneous solid-to-solid rearrangement of covalent oligomers into one macrocyclic product is unprecedented in the solid state.T hese results, we believe,a re an impressive demonstration of the dynamic behavior and self-assembly in organic solids,p otentially adaptable for efficient, selective synthesis of other macrocycles,r educing the need for solvent and acid at least a1 00fold.…”

NMR crystallization: new in situ NMR techniques for time-resolved monitoring of crystallization processes

“…With this motivation, we have developed new in-situ solid-state NMR techniques [1][2][3][4][5][6] that exploit the ability of NMR to selectively detect the solid phase in heterogeneous solid/liquid systems (of the type that exist during crystallization from solution), with the liquid phase "invisible" to the measurement. The technique allows the first solid particles produced during crystallization to be observed and identified, and allows the evolution of different solid phases (e.g.…”