Covalent imine formation

Many biological processes involve an associa tion between two species in a step prior to some subsequent transformation This asso ciation can take many forms It can be a weak associ ation of the attractive van der Waals type or a stronger interaction such as a hydrogen bond It can be an electrostatic attraction between a positively charged atom of one molecule and a negatively charged atom of another Covalent bond formation between two species of complementary chemical re activity represents an extreme kind of association It often occurs in biological processes in which aide hydes or ketones react with amines via imine inter mediates... 

In 2004, Rayner and coworkers reported a dynamic system for stabilizing nucleic acid duplexes by covalently appending small molecules [34]. These experiments started with a system in which 2-amino-2 -deoxyuridine (U-NH ) was site-specifically incorporated into nucleic acid strands via chemical synthesis. In the first example, U-NH was incorporated at the 3 end of the self-complementary U(-NH2)GCGCA DNA. This reactive amine-functionalized uridine was then allowed to undergo imine formation with a series of aldehydes (Ra-Rc), and aldehyde appendages that stabilize the DNA preferentially formed in the dynamic system. Upon equilibration and analysis, it was found that the double-stranded DNA modified with nalidixic aldehyde Rc at both U-NH positions was amplified 34% at the expense of Ra and Rb (Fig. 3.16). The Rc-appended DNA stabilizing modification corresponded to a 33% increase in (melting temperature). Furthermore, imine reduction of the stabilized DNA complex with NaCNBH, resulted in a 57% increase in T. ... 

Partial/complete protein denaturation Covalent alterations Hydrolysis Deamidation Imine formation Racemization Oxidation... 

Aldolases have been classified into mechanistically distinct classes according to their mode of donor activation. Class 1 aldolases achieve stereospecific deprotonation via covalent imine/enamine formation at an active-site lysine residue, while Class II aldolases utilize a divalent transition metal cation for substrate coordination as an essential Lewis acid cofactor (usually Zn ) to facilitate deprotonation... 

Carboxylic acids generated in acylation reactions have been effectively sequestered by ion pair formation with Amberlite IRA-68 ion exchange resin.29 3 Similarly, 4-nitrophenoxide formed in acylations of 4-nitrophenyl esters has been captured by anion exchange with the quaternary ammonium hydroxide resin 12.31 An exception to ion pair-mediated sequestration of byproducts is the polyamine functionalized resin 3 that was shown to covalently sequester the (3-methoxy enone hydrolysis byproduct from Danishefsky s diene via imine formation.23... 

The addition of phenylenediammonium to a mixture of 19 and 21 thus caused two distinct rearrangements to occur initial (covalent) imine exchange followed immediately by (coordinative) ligand exchange, resulting in the exclusive formation of mixed-ligand complex 22. 

Along these lines and as a proof of principle, reversible imine formation was implemented in 1997 for the generation of enzyme (carbonic anhydrase) inhibitors from a dynamic covalent library [43] and reversible covalent selection approaches to catalytic systems were presented [44]. 

A dynamic combinatorial library of six components can be generated under thermodynamic control by imine formation and exchange combined with non-covalent bonding within the enzyme binding site and DCL was evaluated for their relative affinities toward the physiologically relevant human carbonic anhydrase hCA I and hCA II isozymes [66]. 

To rationalize the remarkable regioselectivity and stereoselectivity of these alkylation reactions, Potier and co-workers (777,775) proposed that a stacking interaction occurs between quinone imine 256 and the nucleic acid base prior to covalent bond formation. Moreover, the appropriate intermolecular NOE is observed to support this contention. The fact that these ribonucleotide adducts form so easily may suggest that ellipticine quinone imines could alkylate at the 3 end of transfer RNA or at similar sites on other RNA molecules to inhibit protein synthesis. Thus, RNA would seem to be a reasonable target for elliptinium and related ellipticines (775). 

Jackson, A.W. Stakes, C.H. Fulton, D.A. The formation of core cross-linked star polymer and nanogel assemblies facilitated by the formation of dynamic covalent imine bonds. Polym. Chem. 2011, 2 (11), 2500-2511. 

Organic cage compounds formed by covalent bonds alone have been synthesized with the help of dynamic covalent bond formation. Cage compounds through formation of imine bonds (hemicarcerands, cavitands, adamantoid nano-cages and chiral nano-cubes based on chiral... 

Dynamic covalent chemistry Self-assembly processes that involve reversible covalent bonding such as imine formation. Synonymous with covalent self-assembly. 

Fig. 10 Generation of a set of four multifunctional dynamers PI, P2, P3, and P4 via reversible imine formation between two diamine monomers Ml and M2, and two aldehydes M3 and M4, containing non-covalent supramolecular interaction subunits a donor (Ml), an acceptor (M3), a potential cation binding fragment (Ml and M3) and a neutral linker (the dimethylsiloxane units...

Based on the x-ray crystal structure of the [2]catenane and the DFT-calculated structure of the trefoil knot, the formation of the knotted structures resulted from a strong zinc templated chelation combined with the formation of dynamic covalent imine bonds catalyzed by Zn(II) acting as a Lewis acid and templated by strong tt-tt stacking interactions between the bipyridine of one strand and the phenoxy rings of another—an organization that predisposes the amine functions close to the formyl groups. 

In summary, metal templation and tt-tt stacking interactions were employed cooperatively along with the formation of reversible covalent imine bonds to template the three different links obtained when the two ligands were mixed with zinc. 

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