rXXXX American Chemical Society A dx.doi.org/10.1021/cg1016388 | Cryst. Growth Des. XXXX, XXX, 000–000 ARTICLE pubs.acs.org/crystal Effect of Fluorination on Molecular Conformation in the Solid State: Tuning the Conformation of Cocrystal Formers Tomislav Fri  s  ci  c, † David G. Reid, ‡ Graeme M. Day, † Melinda J. Duer, ‡ and William Jones* ,† † Pﬁzer Institute for Pharmaceutical Materials Science, Department of Chemistry, University of Cambridge, Lensﬁeld Road, Cambridge CB2 1EW, United Kingdom ‡ Department of Chemistry, University of Cambridge, Lensﬁeld Road, Cambridge CB2 1EW, United Kingdom b S Supporting Information ’ INTRODUCTION Pharmaceutical cocrystallization 1,2 and the formation of me- tal-organic frameworks 3 are among the most intensive areas of research in crystal engineering of functional solids. Such interest comes, to a large degree, from the ability to construct functional (e.g., pharmaceutical or porous) materials either by using designs based on supramolecular synthons 4 composed of hydrogen or halogen bonds, 5 or by using isoreticular designs 6 based on the assembly of secondary building units using coordination bonds. 7 However, it is clear that other factors, such as relative shapes and sizes of molecular building blocks, also aﬀect the design of cocrystals and metal-organic frameworks. Consequently, the eﬀect of molecular shape and size on the solid-state arrangement of molecules has also become a subject of intense study. 8,9 In this context, we have previously described how molecular shape and size aﬀect the cocrystallization of the model active pharmaceu- tical ingredient (API) caﬀeine (caf) with succinic acid (Hsuc) (Figure 1a). 10 Speciﬁcally, we have previously observed that cocrystallization of caf with Hsuc occurs only in the presence of a third com- ponent, such as dioxane or chloroform. This third component becomes incorporated into a hydrogen-bonded host lattice constructed from trimeric assemblies (caf) 2 3 (Hsuc). The in- ability of Hsuc and caf to form a binary cocrystal was related to the wheel-and-axle shape 11 of assemblies, known to hinder the close packing of molecules. As a result, (caf) 2 3 (Hsuc) trimers form inclusion hosts by assembling with additional Hsuc or caf (Figure 1b,c). 10 Similarly, caf and adipic acid (Hadi) form a binary (caf) 3 (Hadi) cocrystal in which the wheel-and-axle trimers achieve a close-packed structure by including additional Hadi molecules (Figure 1d). 10,12 The importance of molecular shape in cocrystallization of caf led us to explore perﬂuorinated analogues of Hsu and Hadi, tetraﬂuorosuccinic acid (Hfsu) and octaﬂuoroadipic acid (Hfad) as cocrystal formers (coformers) (Figure 1a). To the best of our knowledge, this is the ﬁrst investigation of aliphatic perﬂuori- nated acids other than triﬂuoroacetic acid as coformers for model APIs, 15,16 although ﬂuorination is a highly eﬀective way to modulate pharmacodynamic and pharmacokinetic properties of Received: December 17, 2009 ABSTRACT: We present a detailed analysis of the eﬀect of ﬂuorination on the conformation of perﬂuorosuccinic acid in the solid state, using database analysis, crystal structure determina- tion, and computational analysis of molecular conformations. Our results indicate that perﬂuorosuccinic acid exhibits strik- ingly diﬀerent conformational preferences to its hydrocarbon analogue despite similarity in molecular size. This diﬀerence in conformational behavior also extends to the pair of adipic and perﬂuoroadipic acids. A search of the Cambridge Structure Database indicates that our analysis is valid for neutral mole- cules, salts, cocrystals, and metal-organic materials, suggesting ﬂuorination as a general means to modify the shape of a molecular building block without changing its size. The diﬀer- ence in molecular shape between hydrocarbon and perﬂuorocarbon molecules is expected to lead to signiﬁcant diﬀerences in solid- state structures of the resulting materials. We illustrate this by comparing the structures of new multicomponent crystals involving the model pharmaceutical ingredient caﬀeine and perﬂuorosuccinic or perﬂuoroadipic acid with the structures of analogous crystals based on the hydrocarbon diacids. Unlike hydrocarbon-based succinic and adipic acids which provide structurally similar hydrogen- bonded cocrystals and inclusion hosts with caﬀeine, perﬂuorosuccinic acid provides a salt and perﬂuoroadipic acid yields a cocrystal. Combined crystal structure analysis, solid-state and solution NMR analysis, single molecule conformational analysis, and calculations of acid dissociation energies indicate that the diﬀerent solid-state behaviors of perﬂuoro- and hydrocarbon acids toward caﬀeine should be interpreted as a result of their distinct conformational properties rather than diﬀerences in pK a values.