emergent consequences of controlling reactivity in ...

From engineering crystals to engineering molecules: emergent consequences of controlling reactivity in the solid state using linear templates

Paper Highlight

Leonard R. MacGillivray* Department of Chemistry, University of Iowa, Iowa City, Iowa 52242-1294, USA. E-mail: [email protected] Received 9th January 2002, Accepted 28th January 2002 Published on the Web 4th February 2002

Molecules that function as linear templates provide a means to organize two molecules, using the principles of molecular recognition and self-assembly, for a bimolecular reaction. The design and application of linear templates in order to direct reactivity in organic solids, particularly [2 1 2] photoreactivity, is outlined. The linear templates provide control of solid-state reactivity such that it is possible, in a similar way to the liquid phase, to conduct molecular synthesis by design.

Introduction The determination by Schmidt that two carbon–carbon (C–C) double bonds undergo an ultraviolet- (UV) induced [2 1 2] cycloaddition reaction in the solid state to form two C–C single bonds according to geometry criteria that define a ‘topochemical principle’1 provides a challenge that presents intriguing synthetic prospects for chemists. In addition to providing stereocontrolled access to molecules less available2 or completely inaccessible in solution, such an approach to synthesis eliminates the need to utilize a toxic organic solvent during a critical covalent-bond-making process, a signature of most organic reactions.3 Unfortunately, however, whereas approaches to solution-phase organic synthesis have evolved such that routes to targeted molecules (e.g. natural products) are being re-examined to improve atom economy and product yield,4 it has remained difficult to control reactivity in the solid state such that reaction homology, a concept central to the development of solution-phase synthesis, has been achieved with limited success.1 Such difficulty has hindered progress in the field such that an ability to systematically construct molecules of desired size, shape, and functionality – a synthetic freedom of the liquid phase4 – has not been generally realized. Leonard R. MacGillivray received his B.Sc. (Hons.) at Saint Mary’s University in Halifax, Nova Scotia, Canada, in 1994. He then obtained his Ph.D. while working in the lab of Jerry L. Atwood at the University of Missouri-Columbia, in 1998. Following his Ph.D., he moved on to a Research Associate position in the Functional Materials Program at the Steacie Institute for Molecular Sciences, National Research Council of Canada, Ottawa, Canada. In 2000, he became an Assistant Professor of Chemistry at the University of Iowa where he pursues interests in supramolecular chemistry and materials science, particularly as they relate to crystal engineering, moleLeonard cular recognition, and host–guest R. MacGillivray chemistry.

The process of controlling reactivity in molecular solids has, moreover, remained one largely based on trial and error, relying upon weak interactions between molecules (e.g. donor– acceptor interactions)5 or constrained environments of cavities (e.g. cyclodextrins)6 to organize reactants into a suitable position for photoreaction.

Linear templates With this in mind, we have introduced a method for controlling [2 1 2] photoreactivity in the solid state that employs molecules that function as linear hydrogen bond templates (Scheme 1).7 Such molecules, using principles of molecular recognition and self-assembly, provide an ability to preorganize8 two molecules within a discrete molecular complex for reaction.9 By enforcing reaction to occur within a zero-dimensional (0D) assembly using the strength and directionality of hydrogen bonds,10 we anticipated that such an approach would eliminate many vexatious problems of intermolecular forces that have made such topochemical designs unreliable, giving us a reliable means of making C–C bonds in solids. Moreover, that the template assembles along the periphery8 of the 0D assembly suggested to us that access to a variety of molecules may be achieved since the template could, in principle, adapt to changes in size (e.g. lengthening) and shape (e.g. bending) of the reactants. By making such changes systematically,1 an ability to conduct molecular synthesis by design, in a similar way to the liquid phase, may be realized.

Solid-state reactivity That C–C bonds, the very foundation of organic chemistry,11 may form in the solid state has been known since the beginning of the last century.1 It was de Jong, in 1923, who postulated that UV irradiation of crystalline cinnamic acid (Fig. 1) induces the molecule to undergo a [2 1 2] cycloaddition to give a truxinic acid consistent with the organization of the molecule in the solid.1

Scheme 1

CrystEngComm, 2002, 4(7), 37-41

DOI: 10.1039/b200332e This journal is # The Royal Society of Chemistry 2002

37

Fig. 1 Solid-state photodimerization of b-cinnamic acid.

From these and related studies involving anthracenes, Schmidt developed topochemical postulates that delineate geometric criteria for the solid-state [2 1 2] photoreaction to occur, ˚ .1 namely, parallel alignment and olefin separation of v 4.2 A Solid-state versus solution-phase synthesis Although geometric criteria for a [2 1 2] photoreaction in the solid state are well established, the ability to organize two double bonds in the solid state for reaction has remained a difficult problem, most methods relying on either substituents5 or auxiliary components6 to ‘steer’ the reactants to the required mode of packing. This difficulty has been largely due to insufficient knowledge of weak interactions that dictate crystal packing (e.g. van der Waals forces).12 Organization of members of an homologous series of compounds, such as R’(CH2)nR@ (n ~ 1,2,3…), for example, is not identical for all values of n in the solid state owing to the sensitivity of crystal packing to unique electronic and steric demands of an individual molecule.1 This has hindered progress in the field such that it has remained difficult for chemists to synthesize molecules in the solid state with degrees of freedom common to solution.4 In effect, products of solid-state [2 1 2] photoreactions have been limited to specific topochemical designs, which, in turn, have thwarted efforts towards targeted molecular synthesis. Approaches to controlling solid-state reactivity Approaches to align olefins in molecular solids for a [2 1 2] photoreaction may be classified into two general categories: methods that employ (1) intramolecular substitution,5 or (2) auxiliary components.6 In the first approach, substitutents are covalently attached to reactants to steer molecules, upon crystallization, into the necessary arrangement for reaction. Schmidt, for example, has revealed that chlorine groups attached to an aromatic ring tend to steer a molecule, by way of Cl…Cl interactions, such that it adopts a b-structure wherein neighbouring olefins are photoactive.5a Following these studies, electrostatic as well as donor–acceptor interactions have been employed for steering the synthesis of molecular and polymeric products (Fig. 2).5b–g Such an approach to controlling reactivity in the solid state, however, has involved steering forces that are relatively weak. This has made the method difficult to control since such forces have difficulty competing with subtle structure demands of dense packing, the driving force that provides the cohesive energy for crystallization.13 In such a context, a ‘J’-shaped dicarboxylic acid has recently been shown to employ an intramolecular approach, by forming a hydrogen-bonded array held together by four O–H…O hydrogen bonds in the form of two carboxylic acid dimers, wherein two olefins conform to the topochemical principle

Fig. 2 Phenyl–perfluorophenyl interactions between two different molecules.

38

CrystEngComm, 2002, 4(7), 37-41

Fig. 3 ‘J’-shaped dicarboxylic acid that forms a hydrogen-bonded assembly.

(Fig. 3).5h UV irradiation produces the expected photoproduct in quantitative yield. Notably, the method utilizes a force (i.e. hydrogen bonding) that is strong enough to compete with relatively weak interactions in molecular solids. Owing to the positioning of the 1,8-substituents, the naphthalene units serve to preorganize8 the olefins within the discrete complex for reaction. In the second approach, an auxiliary component is employed to orient two double bonds for [2 1 2] photoreaction. The auxiliary component is typically in the form of a molecule or cavity. Host cavities based on cyclodextrins6a and saponite,6b for example, have been employed to organize olefins in solids by way of van der Waals and electrostatic forces, respectively. In the former, the host accommodates the guests within a rigid tubular framework whereas, in the latter, the clay-like silicate accommodates the guests by swelling. In each case, the guest dimerizes upon UV irradiation. An auxiliary component that interacts with reactants by way of hydrogen bonds (interactions that, in contrast to van der Waals and electrostatic forces, are both strong and directional) has also been described. Specifically, a family of tetra-aryl diols has been shown to accommodate guests within cavities wherein each host interacts with two guests by way of two O–H…O hydrogen bonds (Fig. 4).6c The guests pack within the cavities created by the hosts such that two olefins of two guests conform to the topochemical principle and photodimerize. Although highly successful, methods that involve cavities require reactants that ‘fit’ within the cavity. This can limit the range of guests (i.e. sizes and shapes) and, therefore, the range of reactants that may be used with a given host system. To address size and shape restrictions of cavities, an approach that utilizes hydrogen bonds and electrostatic forces, in the absence of cavities, has been reported.6d,e Flexible diamines (e.g. ethylenediamine) have been shown to undergo acid–base reactions with cinnamic acids, where each ammonium group forms an N1–H…O2 hydrogen bond with a cinnamate. Combinations of acid and base were found to be photoactive, which was accounted for by formation of threecomponent assemblies where each base, in a syn conformation, forces two anions to conform to the topochemical principle. The dications, however, have been shown in some instances to adopt an anti conformation, where the anions are positioned away from each other and are photostable. The dications have also been shown to participate in additional N1–H…O2 forces

Fig. 4 Tetra-aryl diol that forms cavities and interacts with olefins by way of hydrogen bonds.

with other components of the lattice (e.g. solvent), which disrupts the interaction between cation and anion, producing infinite assemblies that are photostable.14{

Controlling reactivity in the solid state using linear templates Our recently reported approach to controlling [2 1 2] photoreactions in the solid state involves a method that utilizes rigid molecules, in the form of linear hydrogen bond donor templates, to preorganize olefins for reaction within a discrete complex.9 We reasoned that a molecule largely preorganized to orient two double bonds within a 0D molecular assembly for reaction, using the strength and directionality of hydrogen bonds, would largely eliminate consequences of weak intermolecular forces that have made such topochemical designs difficult to control. Moreover, by separating the reacting and steering part of the topochemical design supramolecularly, a flexible means to construct molecules in the solid state may be realized since the template, owing to its reversible interaction with the reactants and its ability to assemble along the periphery of the complex, may be applied to reactants of varying size and shape.

Scheme 2

Fig. 6 Views of (a) 2(res)?2(4,4’-bpe) and (b) 2(1,8-nap)?2(4,4’-bpe).

Selection of templates and reactants That 1,3-disubstituted benzenes and 1,8-disubstituted naphthalenes can organize stacking of aromatics in the solid state, at a ˚ , has been established. Co-crystallization of distance of ca. 4.0 A a bis(resorcinol)anthracene with anthraquinone yielded a 1D hydrogen-bonded array (Fig. 5) where each resorcinol unit lies approximately orthogonal to the quinone and interacts with the stacked dimer by two O–H…O hydrogen bonds.15 As stated, a 1,8-naphthalene has been shown to induce alignment of two double bonds in a solid.5h From these data, resorcinol (res) and 1,8-naphthalenedicarboxylic acid (1,8-nap) were anticipated to function as rigid, linear, hydrogen bond donor templates. With two possible linear templates established, it was clear that the reactants must interact with the template by serving as hydrogen bond acceptors. In such a context, pyridines have been shown to function as hydrogen bond acceptors in solids and to adopt an orthogonal twist with respect to a resorcinol unit.16 As a starting point, trans-1,2-bis(4-pyridyl)ethylene (4,4’-bpe), photostable as a pure solid,17 was chosen as a reactant. Thus, it was anticipated that co-crystallization of 4,4’-bpe with either resorcinol or 1,8-nap would yield four-component complexes, 2(res)?2(4,4’-bpe) and 2(1,8-nap)?2(4,4’-bpe), respectively, held together by four O–H…N hydrogen bonds, where two 4,4’-bpe fragments lie approximately orthogonal to each bifunctional molecule, interacting by way of p–p interactions (Scheme 2). The olefins of each assembly would ˚ . Photobe arranged in a parallel fashion, separated by ca. 4.0 A reaction of each complex would produce, stereospecifically,

Fig. 5 Stacked alignment induced by resorcinol functionality.

{A crown ether has very recently been shown to preorganize two molecules in the solid state for a [2 1 2] photoreaction. The crown ether organized the reactants using a cavity and hydrogen bonds (see ref. 14).

Fig. 7 X-Ray crystal structures of (a) 2(res)?(4,4’-tpcb) and (b) 2(1,8nap)?(4,4’-tpcb).

rctt-tetrakis(4-pyridyl)cyclobutane (4,4’-tpcb).{ Template-directed solid-state synthesis As shown in Fig. 6, co-crystallization of 4,4’-bpe with either resorcinol or 1,8-nap produced discrete, four-component molecular assemblies held together by four O–H…N hydrogen bonds.7a,c In the case of 2(1,8-nap)?2(4,4’-bpe) [Fig. 6(b)], the pyridyl units were observed to participate in C–H…O interactions with the carboxyl moiety.7a As anticipated, the ˚ and olefins of each complex were separated by less than 4.2 A aligned parallel. Notably, olefins of adjacent complexes of each material were organized such that they lie offset. As a result, the olefins of each complex were the sole double bonds of each solid that conformed to the topochemical principle. UV irradiation of a powdered crystalline sample of each material produced 4,4’-tpcb, stereospecifically (100% yield), as determined by 1H NMR spectroscopy. To confirm the structure of each product, a portion of each reacted material was recrystallized from a suitable organic solvent. As shown in Fig. 7, photoreaction of each solid produced 4,4’-tpcb. Interestingly, in the case of 2(res)?2(4,4’-bpe), the template and product assembled to form a discrete three-component assembly, 2(res)?(4,4’-tpcb) [Fig. 7(a)], held together by four O–H…N hydrogen bonds with a structure analogous to that of the unreacted complex. In contrast to 2(res)?2(4,4’-bpe), the components of the reaction involving 2(1,8-nap)?2(4,4’-bpe) assembled to form a 1D hydrogen-bonded chain, 2(1,8nap)?(4,4’-tpcb), where one carboxylic acid group participates {The rctt notation refers to the relative orientation of the substituents of the cyclobutane ring, where r ~ reference, c ~ cis, and t ~ trans.

CrystEngComm, 2002, 4(7), 37-41

39

in an O–H…O hydrogen bond, in the form of a carboxylic acid dimer, with a neighbouring diacid. We attributed the formation of the infinite array to the rigidity of 1,8-nap, which is presumably less able, in contrast to resorcinol, to participate in two O–H…N interactions with two cisoid pyridyl groups of the product. In addition to 4,4’-bpe, we found that this approach could be expanded to trans-1,2-bis(2-pyridyl)ethylene, a reactant that, in a similar way to 4,4’-bpe, is symmetrical, the two hydrogen bond acceptor sites being located adjacent to the reactive centre. We also found that this approach could be expanded to derivatives of resorcinol with substituents unlikely to interfere with the hydrogen bond interaction between the template and reactants (e.g. 5-methoxyresorcinol).7c Molecular solid-state synthesis by design With the realization that this approach permits reliable engineering of C–C bonds in organic solids obtained, we set out to conduct a targeted molecular synthesis.7c Our first target involved a [2.2]paracyclophane (Scheme 3), a member of a class of layered aromatic compounds which has gained much attention owing, in part, to the ability of such molecules to provide challenging targets in organic chemistry, with applications in synthetic chemistry (e.g. catalysis) and materials science (e.g. optical materials).18 Specifically, we anticipated that co-crystallization of resorcinol or 1,8-nap, or a derivative, with the lengthened reactant 1,4-bis[2-(4-pyridyl)ethenyl]benzene (1,4-bpeb)19 would yield a four-component molecular assembly where two olefins, separated by a benzene spacer, would be positioned for photoreaction. UV irradiation of the solid was expected to give a tricyclic product with an inner cyclic core reminiscent of a [2.2]paracyclophane. The periphery of the paracyclophane would, in effect, possess an imprint of the template along its exterior.20 Moreover, such an approach would provide a novel entry to cyclic molecules where low yields often requiring high dilution conditions (i.e. large batches of solvent) are common in solution.21 The product of the co-crystallization of 1,4-bpeb with 5-methoxyresorcinol (5-OMe-res) is shown in Fig. 8. As anticipated, the components assembled to form a discrete four-component complex, 2(5-OMe-res)?2(1,4-bpeb), held together by four O–H…N hydrogen bonds. In this arrangement, the olefins of 1,4-bpeb, one of which is disordered across two positions (occupancies 70 : 30), are aligned within the complex such that the olefin of the major site conforms to the topochemical principle with the ordered olefin, the two ˚ . Two ordered olefins double bonds being separated by 3.70 A of the two nearest neighbour assemblies were, notably, found ˚. to lie parallel and within 3.95 A UV irradiation of 2(5-OMe-res)?2(1,4-bpeb) produced the [2.2]paracyclophane (60%), along with a monocyclized dimer (30%) and indefinable products (10%). The cyclophane was characterized by three pairs of doublets that correspond to the

Scheme 3

40

CrystEngComm, 2002, 4(7), 37-41

Fig. 8 X-Ray crystal structure of 2(5-OMe-res)?2(1,4-bpeb): (a) side-on view, and (b) overhead view.

pyridyl, phenylene, and cyclobutane protons. The splitting pattern of the phenylene moiety is indicative of an exo, rather than an endo, isomer, while the relatively high yield of the [2.2]paracyclophane is consistent with a dynamic model of disorder. Moreover, the template-directed solid-state synthesis occurred regio- and stereo-selectively, proceeding by way of a monocyclized product where the indefinable materials are attributed to reactions involving nearest neighbour complexes.

Summary and outlook An approach to controlling reactivity in the solid state using linear hydrogen bond templates has been described.7 By using principles of molecular recognition and self-assembly, an ability to conduct molecular synthesis by design4 has been outlined. With these observations achieved, studies to elucidate further the fundamentals of this approach are currently underway such that the solid state may be used for controlling the targeted synthesis of molecules of increasing complexity.22 Indeed, such an ability to deliberately place molecules in a position for reaction may provide an entry to molecular frameworks of nanometre-scale dimensions, where the stereocontrol offered by such an approach could overcome problems of molecular entanglement that can lead to poor selectivities and product yields.23 Moreover, with a flexible means to make C–C bonds in the solid state using linear templates being achieved, it is anticipated that, in similar way to the liquid phase, applications of products of the approach may be developed, where access to molecules, and materials, with properties that extend beyond the reach of more conventional synthetic methodologies9 may be realized.

Acknowledgements Funding for this research was provided by the University of Iowa and the Natural Sciences and Engineering Research Council of Canada (research grant).

Notes and references 1 G. M. J. Schmidt, Pure Appl. Chem., 1971, 27, 647. 2 E. Cheung, T. Kanf, J. R. Scheffer and J. Trotter, Chem. Commun., 2000, 2309. 3 P. T. Anastas and J. C. Warner, Green Chemistry: Theory and Practice, Oxford University Press, New York, 1998. 4 K. C. Nicolaou, Angew. Chem., Int. Ed., 2001, 39, 44. 5 (a) J. A. R. P. Sarma and G. R. Desiraju, Acc. Chem. Res., 1986, 19, 222; (b) G. W. Coates, A. R. Dunn, L. M. Henling, J. W. Ziller, E. B. Lobkovsky and R. H. Grubbs, J. Am. Chem. Soc., 1998, 120, 3641; (c) C. V. K. Sharma, K. Panneerselvam, L. Shimoni, H. Katz, H. L. Carrell and G. R. Desiraju, Chem. Mater., 1994, 6, 1282; (d) Y. Maekawa, S. Kato and M. Hasegawa, J. Am. Chem. Soc., 1991, 113, 3867; (e) K. Gnanaguru, N. Ramasubbu, K. Venkatesan and V. Ramamurthy, J. Org. Chem., 1985, 50, 2337; (f) G. R. Desiraju, R. Kamala, B. H. Kumari and J. A. R. P. Sarma, J. Chem. Soc., Perkin Trans. II, 1984, 181; (g) W. Jones, H. Nakanishi, C. R. Theocaris and J. M. Thomas, J. Chem. Soc., Chem. Commun., 1980, 610; (h) K. S. Feldman and R. F. Campbell, J. Org. Chem., 1995, 60, 1924.

6 (a) T. J. Brett, J. M. Alexander, J. L. Clark, C. R. Ross II, G. S. Harbison and J. J. Stezowski, Chem. Commun., 1999, 1275; (b) K. Takagi, H. Usami, H. Fukaya and Y. Sawaki, J. Chem. Soc., Chem. Commun., 1989, 1174; (c) K. Tanaka, F. Toda, E. Mochizuki, N. Yasui, Y. Kai, I. Miyahara and K. Hirotsu, Angew. Chem., Int. Ed., 1999, 38, 3523; (d) Y. Ito, B. Borecka, J. Trotter and J. R. Scheffer, Tetrahedron Lett., 1995, 36, 6083; (e) Y. Ito, B. Borecka, G. Olovsson, J. Trotter and J. R. Scheffer, Tetrahedron Lett., 1995, 36, 6087. 7 (a) G. S. Papaefstathiou, A. J. Kipp and L. R. MacGillivray, Chem. Commun., 2001, 2462; (b) G. S. Papaefstathiou and L. R. MacGillivray, Org. Lett., 2001, 3, 3835; (c) L. R. MacGillivray, J. L. Reid and J. A. Ripmeester, J. Am. Chem. Soc., 2000, 122, 7817. 8 D. J. Cram, Science, 1982, 240, 760. 9 S. Anderson and H. L. Anderson, in Templated Organic Synthesis, F. Diederich and P. J. Stang, ed., Wiley-VCH, New York, 2000, pp. 1–38. 10 G. R. Desiraju, Nature, 2001, 412, 397. 11 T. M. Trnka and R. H. Grubbs, Acc. Chem. Res., 2001, 24, 18. 12 G. R. Desiraju, Crystal Engineering, Elsevier, New York, 1988. 13 K. T. Holman and M. D. Ward, Angew. Chem., Int. Ed., 2000, 39, 1653. 14 D. G. Amirsakis, M. A. Garcia-Garibay, S. J. Rowan,

15

16 17 18

19

20 21 22 23

J. F. Stoddart, A. J. P. White and D. J. Williams, Angew. Chem., Int. Ed., 2001, 40, 4256. Y. Aoyama, K. Endo, T. Anzai, Y. Yamaguchi, T. Sawaki, K. Kobayashi, N. Kanehisa, H. Hashimoto, Y. Kai and Y. Masuda, J. Am. Chem. Soc., 1996, 118, 5562. L. R. MacGillivray and J. L. Atwood, J. Am. Chem. Soc., 1997, 119, 6931. J. Vansant, S. Toppet, G. Smets, J. P. Declercq, G. Germain and M. Van Meerssche, J. Org. Chem., 1980, 45, 1565. J. Kleinschroth and H. Hopf, Angew. Chem., Int. Ed. Engl., 1982, 21, 469; J. Nishimura, Y. Nakamura, Y. Hayashida and T. Kudo, Acc. Chem. Res., 2000, 33, 679. A. J. Amoroso, A. M. W. C. Thompson, J. P. Maher, J. A. McCleverty and M. D. Ward, Inorg. Chem., 1995, 34, 4828. H. Asunuma, T. Hishiya and M. Komiyama, Adv. Mater., 2000, 12, 1019. V. Prautzsch, S. Ibach and F. Vo¨gtle, J. Inclusion Phenom. Macromol Chem., 1999, 33, 427. K. E. Drexler, Proc. Natl. Acad. Sci. USA, 1981, 78, 5275. C.-T. Chen, P. Gantzel, J. S. Siegel, K. K. Baldridge, R. B. English and D. M. Ho, Angew. Chem., Int. Ed. Engl., 1995, 34, 2657.

CrystEngComm, 2002, 4(7), 37-41

41