Perspective Supramolecular templating in thermodynamically controlled synthesis Ricardo L. E. Furlan*, Sijbren Otto†‡, and Jeremy K. M. Sanders†‡ *Universidad Nacional de Rosario, Facultad de Ciencias Bioquı´micasy Farmace´uticas, Suipacha, 531, 2000 Rosario, Argentina; and †Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom his perspective has a simple message: lar recognition has become a versatile tool TCovalent synthesis under thermody- that enables control over equilibrium sys- namic control can be a powerful tool for tem. Selective recognition of one of the preparing mechanically interlocked struc- components in an equilibrium system will tures and specific macrocycles in high result in the creation of an additional well in yield and at the same time serve as an the Gibbs energy landscape (Fig. 1). If this engine for the creation of dynamic com- well is deep enough, the recognized com- binatorial libraries (DCLs), which are re- pound will dominate the mixture at the sponsive to their environment. Here we expense of undesired products. In practice will highlight some examples that illus- this outcome requires addition of a species trate the potential of thermodynamically (a template) that selectively recognizes, controlled covalent chemistry and we will binds, and stabilizes the desired compound. point out some exciting directions for the In a sense, this template plays a role similar future. A more comprehensive review of to that of a catalyst in kinetically controlled the area has been provided elsewhere (1). synthesis. Most of the reactions used in organic Despite the fact that equilibrium sys- synthesis are irreversible in practice. The tems seem much more tractable than ki- Fig. 1. Free energy landscape of an equilibrium outcome of a given procedure is determined netically controlled transformations, rela- mixture showing the effect of adding a template that strongly and selectively binds to one of the by the kinetics of the desired reaction as well tively little use has been made of them so equilibrating species. as the kinetics of the undesired competing far in synthesis. Although there are good processes. Hence, yields and product distri- reasons not to strive for equilibrium dis- PERSPECTIVE butions reflect the relative differences be- tributions in many instances, there are are summarized in Fig. 2. They can be tween the various initial and transition-state other cases where thermodynamically divided into two categories, depending on Gibbs energies. Optimization of such kinet- controlled synthesis is the way forward. In the symmetry of the reversible linkage. ically controlled processes involves changing particular, thermodynamic control is Disulfide exchange (2, 3) and alkene the Gibbs energies of initial states or, more highly advantageous in the synthesis of metathesis (4) are symmetrical. Disulfide frequently, transition states. Impressive macrocycles and mechanically interlocked exchange is mediated by a catalytic achievements have been made following compounds. Also, combinatorial chemis- amount of thiolate anion attacking the this approach mainly through the use of try is more versatile when operated under existing disulfide bonds. Exchange pro- SPECIAL FEATURE catalysts. Nevertheless, improving kineti- thermodynamic control. As we will show ceeds readily under neutral to mildly basic cally controlled reactions has been and still below, dynamic combinatorial chemistry conditions, whereas acidifying the me- remains a challenge, largely as a result of the enables high-yield synthesis of, for in- dium causes protonation of the thiolate elusive nature of the activated complex, stance, a host molecule in one step with- anion and turns off exchange (2, 3). which does not lend itself to direct study. out prior knowledge of its exact structure. Alkene metathesis (4) is controlled The situation is further complicated by Reversible Covalent Chemistry through addition or removal of a catalyst. the fact that effects on the Gibbs energy The usefulness of this reaction has been of the initial state need to be taken into A major reason why the use of reversible increasing rapidly, as new, more efficient, consideration. covalent chemistry is not more widespread and general catalysts become available. For thermodynamically controlled reac- is the rather limited number of reversible Reversible reactions that feature un- tions the situation is much less complex. reactions available. Furthermore, many re- symmetrical linkages include amide ex- Product distributions now depend on only actions are reversible only under conditions change (5), transesterification (6–8), as the relative Gibbs energies (stabilities) of that are not compatible with the subtle well as exchange of imines (9, 10) and the products themselves. Of course, chem- noncovalent interactions involved in tem- ists have long made use of the fact that plating. Finally, after the equilibrium distri- derivatives thereof. Only one example of product distributions of some reactions are bution has been reached it must be possible amide exchange has been reported (5), under kinetic control under one set of con- to turn off the reversible reaction to isolate making use of enzymes to cleave and ditions, whereas the thermodynamic prod- and handle the desired product. In practice reform the amide bonds. Transesterifica- uct prevails under other conditions. But why this is most often accomplished by removal tion has received more attention. Unfor- not go one step further and actively manip- of the catalyst responsible for reversibility or tunately, this reaction generally requires ulate the Gibbs energies of the products so by altering the pH of the solution. harsh conditions that are likely to inter- as to shift the equilibria in any desired The reversible reactions that have thus direction? With the increased understand- far been used successfully in templated ‡To whom reprint requests should be addressed. E-mail: ing of supramolecular interactions, molecu- thermodynamically controlled synthesis [email protected] or [email protected]. www.pnas.org͞cgi͞doi͞10.1073͞pnas.022643699 PNAS ͉ April 16, 2002 ͉ vol. 99 ͉ no. 8 ͉ 4801–4804 Downloaded by guest on September 24, 2021 plate recognition. Oximes (11) and hydra- also respond to exterior influences. The zones (12) do not suffer from this disadvan- more fundamental of those influences, such tage. In these cases, exchange requires acid as temperature, pressure, and effects of and is switched off after neutralization to solvents and extents of ionization of the yield a robust product. molecules, has received relatively little at- tention in the area of small molecule syn- Manipulating Equilibria thetic chemistry. Yet these parameters Reactions that are most likely to benefit might well prove to be useful handles in from being controlled by thermodynamics optimizing the proportion of desired prod- are processes such as macrocyclizations uct in equilibrium mixtures. where several products are accessible that More specific manipulation of an equi- differ in size rather than connecting chem- librium composition is possible by exposing istry. Ring-closure reactions performed un- the system to templates. Two types of tem- der kinetic control are notorious for giving plating approaches can be distinguished. In relatively large amounts of unwanted oligo- the synthesis of mechanically interlocked meric side products even under high- structures the template will usually be part dilution conditions. Under thermodynamic of the final product.§ Alternatively the tem- Fig. 2. Reversible reactions that have been used control, the product distribution of the same plate can be used simply as a mould, in successfully in thermodynamically controlled reaction is governed only by the stabilities of which case it will be removed once the synthesis. the different macrocycles. These stabilities equilibrium is frozen, giving access to the are partly determined by interactions within free receptor molecule. Even though these the macrocycles (e.g., ring strain) and partly approaches lead to topologically different fere with the weak interactions underlying by the concentration at which the reaction is products, they share two necessary features: recognition by a template (6, 7). In the carried out. Disregarding ring strain, rela- (i) a template effect that stabilizes the de- special case of allyl esters, Pd-catalyzed tively dilute conditions (less than 10 mM) sired product via supramolecular interac- transesterification proceeds under mild will favor smaller ring sizes (13). Higher tions and (ii) one or more reversible con- conditions (8). oligomers might still be formed in the initial nections allowing for proofreading and Reactions based on exchange around the stages of the reaction but they will be con- editing of undesired products (Fig. 3). C ϭ N bond are more versatile. The parent sumed as equilibrium is approached. As imines can be used, but they suffer from an concentrations are raised, the product dis- Thermodynamically Controlled Synthesis of inherent instability. Reduction of the imines tribution will gradually shift toward higher Mechanically Interlocked Structures. The in- to amines is generally required to stop the oligomers, culminating in polymer forma- terest in mechanically interlocked structures equilibration process and allow for isolation tion for very concentrated solutions (for a like catenanes (interlocked rings) and rotax- of the product (9, 10). These final amines are review of