This is the author-version of a paper published as: Smith, G., Wermuth, U. D., Healy, P. C., and White, J. M., "Molecular Recognition in Proton-Transfer Compounds of Brucine with Achiral Substituted Salicylic Acid Analogues," Aust. J. Chem., 2006, 59, 320-328 For definitive published version, see: http://dx.doi.org/10.1071/CH06074 © CSIRO 2006 Molecular Recognition in Proton-Transfer Compounds of Brucine with Achiral Substituted Salicylic Acid Analogues Graham Smith A , D , Urs D. Wermuth A , Peter C. Healy B and Jonathan M. White C A School of Physical and Chemical Sciences, Queensland University of Technology, Brisbane QLD 4001, Australia. B School of Science, Griffith University, Nathan QLD 4111, Australia. C School of Chemistry, University of Melbourne, Parkville VIC 3052, Australia. D Corresponding author. Email: [email protected] Abstract The 1:1 proton-transfer brucinium compounds from the reaction of the alkaloid brucine with 5-nitrosalicylic acid, 3,5-dinitrosalicylic acid, and 5-sulfosalicylic acid, namely anhydrous brucinium 5-nitrosalicylate (1), brucinium 3,5-dinitrosalicylate monohydrate (2), and brucinium 5-sulfosalicylate trihydrate (3) have been prepared and their crystal structures determined by X-ray crystallography. All structures further demonstrate the selectivity of brucine for meta-substituted benzoic acids and comprise three-dimensional hydrogen-bonded framework polymers. Two of the compounds (1 and 3) have the previously described undulating brucine sheet host-substructures which incorporate interstitially hydrogen-bonded salicylate anion guest species and additionally in 3 the water molecules of solvation. The structure of 2 differs in having a three-centre brucinium–salicylate anion bidentate N+–H···O(carboxyl) hydrogen- bonding association linking the species through interstitial associations involving also the water molecules of solvation. A review of the crystallographic structural literature on strychnine and brucine is also given. The Strychnos alkaloids strychnine (strychninidin-10-one) and its 2,3-dimethoxy- substituted analogue brucine (Scheme 1) were first reported by Fischer[1] in 1899 as agents for the separation of enantiomeric mixtures of the optically active N-benzoyl- protected alanines. Optical resolution using these alkaloids and various other resolving agents has over the intervening years been largely a trial-and-error process although a systematization of the methods has evolved.[2] Both strychnine and brucine exhibit almost identical physicochemical and physiological properties (e.g. pKa1 6.04 (N9); pKa2 11.7 (N19)),[3] but with respect to resolving potential brucine has proved to be the better one, with a brucine/strychnine incidence of 22 to 8 among compounds with chiral organic molecules, and 14 to 3 with achiral organic molecules, among the 47 known crystallographically characterized structures. Because of the relatively high base strength of the N19 atom, reaction with many acids will occur, resulting in proton transfer with the subsequent generation of a cationic strychninium or brucinium species. This is evident in the high proportion of proton-transfer compounds among the known structures. Such compounds are important in many biological transfer processes and these alkaloids in their protonated forms may also be involved in their mode of toxic action. Although the two compounds differ only in the presence, in brucine, of the two methoxy groups, these appear to influence the formation of a relatively common undulating sheet host-substructure which is present in several proton-transfer and neutral organic brucine structures, including the solvates. In all of the reported examples, the two methoxy groups assume the same conformation, being anti-related and lying in the plane of the benzene ring. Accommodated within the host inter-sheet spaces are complementary guest molecules (anions, adduct, and solvent molecules), which associate with the brucine host-framework through hydrogen-bonding interactions. This structure type provided an early example of molecular recognition first described by Gould and Walkinshaw in 1984,[4] with the structure of the brucinium salt of the Fischer-type N-benzoyl-protected d-alanine. This feature is not present in the structure of the analogous strychnine salts of d- or l-alanine.[5] The brucine solvate structures brucine–ethanol–water (1/1/2,[6] found to be isomorphous with brucine–isopropanol–water 1/1/2[7]) also show the guest molecules accommodated within the interstitial cavities, acting in a space-filling capacity but hydrogen-bonded to the nitrogen acceptor sites of the brucine host. This substructure is also found in the structure of anhydrous brucine[7] where there is no interstitial guest spatial requirement, but not in the minimally associative brucine–acetone (1/1) solvate.[7] In the case of compounds with acidic organic molecules, proton-transfer to N19 of the brucine or strychnine molecule occurs and the resultant site acts as a donor site for hydrogen-bonding association with the guest molecule. In the structure of brucinium–3-nitrobenzoate–methanol (1/1/1), Oshikawa[8] also demonstrated a selectivity of brucine for the meta-substituted benzoic acids which included the meta- chloro- and meta-bromo-substituted analogues, whereas no interaction was given with the ortho- or para-isomers. The rigid stereochemistry of the strychnine and brucine cage is considered to be an important contributing factor to the regularity particularly of the brucine substructures and a large number of crystal structures of the resultant cocrystals have been reported. The X-ray crystal structure determination of strychninium bromide dihydrate by Robertson and Beevers in 1951[9] confirmed the Robinson and Woodward molecular structure,[10,11] and subsequently the structures of several inorganic strychninium compounds and their analogues have now been determined. These include the sulfate, nitrate, chloride, iodide, perchlorate, hydrogensulfate, dihydrogenphosphate, and the hexasulfide, whereas the structure of brucinium sulfate has only recently been reported.[12] As well, the structures of the anhydrous parent compounds strychnine[6,13] and brucine[7] have been determined as have those of other substituted strychnines.[14] We have categorized the organic strychnine and brucine compounds as follows: (a) Those with chiral acidic species, giving mostly 1:1 proton-transfer compounds. (b) Those with chiral neutral species, giving molecular adducts. (c) Those with achiral acidic species also giving proton-transfer compounds; this category contains occasional 2:1 compounds with strong diprotic acids. (d) Those with achiral neutral species. In all of these the absolute configuration determined by Peerdeman[15] is invoked, giving for the six chiral centres of neutral strychnine or brucine the Cahn–Ingold– Prelog designation[16] of the molecules as C7(R), C8(S), C12(S), C13(R), C14(R), C16(S). Of the four categories of compounds, totalling 47 organic strychnine and brucine compounds referenced in this work, category (a) contains a larger proportion of the examples (51%) because these compounds are more often the types giving good crystalline materials with strychnine and brucine in enantiomorph resolution. Examples include the strychninium and brucinium salts of the N-benzoyl-protected alanines,[4,5] the N-phthaloyl-protected alanines,[17] N-acetyl-protected l- tryptophane,[18] as well as those of the N-phthaloyl-β-hydroxy-d- and l-leucines (three compounds).[19] Other chiral acid types include hydroxy acids: d-glucuronic and d-galacturonic acids (both with brucine),[20] both d- and l-tartaric acid (with strychnine),[21] a disaccharide acid,[22] l-glyceric acid,[23] l-malic acid,[24] l- tartaric acid,[24] and citric acid[25] (latter five all with brucine), other miscellaneous acid types (all with brucine),[26–32] a phosphodithiol salt with methylstrychnine,[33] as well as S-(+)-bromochlorofluoroacetate with strychnine.[34] With these proton- transfer compounds, the protonated N19 of the strychnine or brucine molecule subsequently generates another chiral centre in the cation (S).[16] In category (b) (15%), the types of compound giving neutral adducts include those with chiral alcohols (both with brucine),[35,36] lactones (all with brucine),[8,37–39] and cyanohydrins (two with brucine).[40] Falling into categories (c) and (d) are the structures of several compounds of strychnine and brucine with achiral acidic and neutral organic molecules. The proton-transfer compounds again comprise the larger group, the category (d) examples (8.5%) being limited to the brucine solvates with acetone, ethanol, and isopropanol,[6,7] with isopropanol also being a common inclusion molecule in brucine salts.[41] We also reported the first example of a brucine or strychnine compound with a zwitterionic acid species in the hydrated strychnine adduct with the achiral 1,7-Cleve’s acid (8-amino-2-naphthalenesulfonic acid).[42] The category (c) examples, comprising 25.5% of the total are as follows: brucinium– 4-hydroxybenzoate–isopropanol (1/1/1),[41] brucinium 4-nitrophenate,[43] brucinium hydrogen fumarate sesquihydrate and brucinium hydrogen maleate,[44] brucinium– 2,2′-bis(3-phenyl-1-naphthol)phosphate–ethanol–water (1/1/1/2),[45] brucinium–2,2- dimethoxy-1-oxonaphthalene-4-carboxylate–2,2-dimethoxy-1-oxonaphthalene-4- carboxylic acid (1/1/1),[46] and brucinium 3-nitrobenzoate.[8] Because of the demonstrated selectivity shown by brucine for meta-substituted benzoic acids, we subsequently