Self-sorting of dynamic imine libraries during distillation.

Nature and chemists approach organic synthesis in very different ways. Living systems are grand masters of parallel synthesis: starting with incredibly complex precursor mixtures, highly specialized enzymes operate selectively, simultaneously, and orthogonally to create many different products at once. In contrast, laboratory synthesis typically relies on reagents and catalysts with broad scope and wide functionalgroup tolerance; in this case, high-purity starting materials are required for the sequential preparation of individual products. Furthermore, undesirable reactivity often has to be blocked by protecting groups. In recent years, self-sorting has emerged as a promising preparative method that can enable the simultaneous synthesis of high-purity products from complex mixtures of starting materials. Self-sorting can be defined as the spontaneous reorganization of a disordered multicomponent system into a set of subsystems with fewer components and greater order. In the absence of specific enzyme catalysis, high fidelity of synthetic self-sorting is ensured by efficient error-correction mechanisms, which use the reversible formation of noncovalent and dynamic covalent bonds to continuously recycle side products as the system heads towards equilibrium. Self-sorting processes can proceed under thermodynamic 5] or kinetic control. The former processes are characterized by a self-sorted equilibrium state; the latter are less common and are typically observed when a system is trapped in a self-sorted local energetic minimum. We recently reported a hybrid selfsorting protocol in which components of a dynamic imine mixture freely equilibrate (thermodynamic control), and sort on the basis of the rates of their removal from equilibrium through an irreversible reaction (kinetic control). The synthetic applicability of self-sorting is frequently limited by the fact that all self-sorted species remain in the same solution. The isolation of individual components requires separation, which can be problematic in the case of fragile supramolecular complexes. Herein, we demonstrate that the self-sorting of dynamic mixtures can occur concurrently with separation to produce multiple products that are not only of high purity, but also mechanically separated. Specifically, we show that vacuum distillation can be used to sort complex libraries of [n n] equilibrating imines (n 5) into n pure compounds simply on the basis of the volatility of individual imines. Imines are formed in a reversible reaction of an aldehyde with an amine. When multiple imines are present in a solution, they readily exchange their aldehyde and amine constituents. In any such equilibrating mixture, one imine has the lowest boiling point. If that compound can be distilled away selectively, its removal disturbs the equilibrium of the system and thus forces other imines to reequilibrate and produce more of the compound just removed—as dictated by the Le Ch telier principle. Provided that distillation is sufficiently selective and slower than the imine exchange, the low-boiling imine will extract its constituent aldehyde and amine from all other imines that contained them. In the process, the low-boiling imine is produced in superior yield, and the remaining equilibrating mixture is reduced in complexity through the removal of both the low-boiling imine and all its precursors. If such a sequence is repeated, multiple species can be produced with a single distillation setup. We assessed the synthetic viability of this proposition in an experiment which examined the behavior of a mixture prepared from two aromatic aldehydes 1 and 2 and two anilines A and B (Scheme 1). To ensure that the resulting imines had significantly different boiling points, we chose aldehydes and anilines of different molecular masses and assumed that a higher mass would lead to a higher boiling point. The heating of these four reactants under dehydrative conditions produced a mixture of all possible imines: 1A, 2A, 1B, and 2B. The most volatile of the four was 1A—the product of the reaction of the lighter aldehyde with the lighter aniline; conversely, the least volatile imine was the product 2B of the heavy–heavy combination. Vacuum distillation (90– 115 8C, 0.10 mmHg) of this mixture began with the selective removal of low-boiling 1A. With the depletion of 1A, 2A and 1B started decomposing to produce more of 1A ; eventually, these two compounds were completely consumed in the process, and the only imine remaining in the distillation flask was 2B. Compounds 1A (most volatile, light distillation fraction) and 2B (least volatile, heavy distillation fraction) were isolated in virtually quantitative yield (96 and 98%, respectively) and in very high purities, as evidenced by H NMR spectroscopy (98 and 99%, respectively; see the Supporting Information for details). Three additional higher-boiling [2 2] combinations (see the Supporting Infor[*] Dr. K. Osowska, Prof. O. Š. Miljanić Department of Chemistry, University of Houston Houston, TX 77204-5003 (USA) E-mail: [email protected] Homepage: http://www.miljanicgroup.com