Highly Selective Monomethylation of Primary Amines Through Host−Guest Product Sequestration

Yebeutchou, Roger M.; Dalcanale, Enrico

doi:10.1021/ja809614y

Cited by 68 publications

(44 citation statements)

References 34 publications

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“…By the appropriate choice of substrates with complementary interactions with the host molecule, large rate accelerations, changes in selectivity, or shifts in the thermodynamic properties of encapsulated guests have been demonstrated. [10][11][12][13][14][15] In this Accounts paper, we document how the hydrophobic cavity of a selfassembled supramolecular host is able to thermodynamically shift the acid-base equilibrium of encapsulated guests and how we translated this stabilization into chemical catalysis. …”

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Proton-Mediated Chemistry and Catalysis in a Self-Assembled Supramolecular Host

2009

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Synthetic supramolecular assemblies able to encapsulate guest molecules often impart unique reactivity on the encapsulated guests. Although much less complex than the active sites of enzymes, synthetic host molecules have been developed that can carry out complex reactions within their cavities.Over the last decade, the Raymond group has developed a series of self-assembled supramolecules able to encapsulate small guest molecules. This Account details recent collaborative work between the Raymond and Bergman groups focusing on chemical catalysis stemming from the encapsulation of protonated guests and expanding to acid-catalysis in basic solution.We initially investigated the ability of a self-assembled supramolecular host molecule to encapsulate protonated guests. Our study of encapsulated protonated amines revealed a rich array of host-guest chemistry. Guest exchange studies established that the rates of encapsulated protonated amines were dependent on the steric bulk of the amine rather than its basicity. The purely-rotational T symmetry of the host molecule effectively desymmetrized the geminal N-methyl groups and allowed for the observation and quantification of the barriers for nitrogen inversion followed by bond rotation. In further screening of amine guests, small nitrogen heterocycles such as N-alkylaziridines, -azetidines and -pyrrolidines were found to be encapsulated as proton-bound homodimers or homotrimers. Expanding 3 the study of protonated amines to investigate the thermodynamic stabilization of protonated amines showed that encapsulation makes the encapsulated amines more basic and raises the effective basicity of the protonated amines by up to 4.5 pK a units.The thermodynamic stabilization of protonated guests was translated into chemical catalysis by applying the stabilization of protonated species to reactions proceeding through monocationic protonated intermediates. Orthoformates, which are generally stable in neutral or basic solution, were found to be suitable substrates for catalytic hydrolysis by the assembly. Orthoformates small enough to undergo encapsulation were readily hydrolyzed by the assembly in basic solution with observed rate accelerations of up to 3900 when compared to the uncatalyzed reaction. Furthering the analogy to enzymes that obey Michaelis-Menten kinetics, competitive inhibition was demonstrated with the inhibitor NPr 4 + , thereby confirming that the interior cavity of the assembly was the active site for catalysis. Mechanistic studies revealed that the assembly is intimately required for catalysis and that the rate limiting step of the reaction is proton-transfer from hydronium to the encapsulated substrate.Encapsulation in the assembly changes the orthoformate hydrolysis mechanism from an A-1, in which decomposition of the protonated substrate is the rate limiting step, to an A-S E 2 mechanism in which proton transfer is the rate limiting step. The study of hydrolysis reactions in the assembly was next extended to acetals, which were also catalytically hydrolyzed ...

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Proton-Mediated Chemistry and Catalysis in a Self-Assembled Supramolecular Host

2009

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“…However, there has been little progress in using container molecules as a means of protection. Indeed, to our knowledge, there has been only one reported example of supramolecular protection, where a primary amine product was prevented from over-alkylation by complexation to a cavitand24.…”

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Kinetic resolution of constitutional isomers controlled by selective protection inside a supramolecular nanocapsule

et al. 2010

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The concept of self-assembling container molecules as yocto-litre reaction flasks is gaining prominence. However, the idea of using such containers as a means of protection is not well developed. Here, we illustrate this idea in the context of kinetic resolutions. Specifically, we report on the use of a water-soluble, deep-cavity cavitand to bring about kinetic resolutions within pairs of esters that otherwise cannot be resolved because they react at very similar rates. Resolution occurs because the presence of the cavitand leads to a competitive binding equilibrium in which the stronger binder primarily resides inside the host and the weaker binding ester primarily resides in the bulk hydrolytic medium. For the two families of ester examined, the observed kinetic resolutions were highest within the optimally fitting smaller esters.The simple act of compartmentalization is essential to chemistry. To an organic chemist, a round-bottomed flask is both a means of promoting a reaction by keeping reagents in, and stopping reactions by keeping species such as adventitious water out. In parallel with these concepts, in recent years supramolecular chemists have developed the idea of using container molecules as yocto-litre flasks to promote new reactions . However, there has been little progress in using container molecules as a means of protection. Indeed, to our knowledge, there has been only one reported example of supramolecular protection, where a primary amine product was prevented from over-alkylation by complexation to a cavitand 24 .While considering the idea of protection via compartmentalization, it occurred to us that one of the strengths of container molecules that fully envelop their guests is their ability to recognize subtle differences between the gross overall forms of molecules. Consequently, many of the container molecules in the literature could theoretically bring about not just the familiar kinetic resolution of stereoisomers [25][26][27][28] , but also the as yet unexplored topic of the kinetic resolution of constitutional isomers. Regarding the latter, there are of course many examples of compounds only being available as mixtures with constitutional isomers or constitutionally similar molecules. Hence, establishing a proof-of-principle that container molecules could effect such purifications could be quite powerful. In this Article, we report on the ability of supra-molecular nanocapsules to bring about the kinetic resolution of constitutionally isomeric long-chain esters. More specifically, we show that the capsule formed by water-soluble host * Correspondence and requests for materials should be addressed to B.C.G. bgibb@uno.edu. Author contributionsB.C.G. and S.L. conceived and designed the experiments. S.L. synthesized esters 2-6 and performed the experiments involving these guests. H.G. and A.T.H contributed equally to the syntheses and experiments involving esters 7-11. B.C.G. wrote the paper. Additional informationThe authors declare no competing financial interests. Supplementa...

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“…(2) To clarify the gas-phase properties of complexes formed by phosphonate cavitands, [9] since one of their applications is gas sensing [10]. The earlier reported results have shown that the phosphonate cavitands are capable of selectively forming complexes with alcohols [11][12][13][14] and ammonium ions [7,15,16], which has just recently led to application of phosphonate cavitands in supramolecular polymers [17], molecular recognition on silicon surfaces [18], and product protection in amine methylation reactions [19]. Number and positioning of the P ϭ O groups at the upper rim and their relative orientation with respect to the cavity are the key host parameters in defining the multiple H-bonding interactions involved in the recognition process [16].…”

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Hydrogen bonding in phosphonate cavitands: Investigation of host-guest complexes with ammonium salts

Kalenius

Neitola

Suman

et al. 2010

J. Am. Soc. Mass Spectrom.

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The H-bonding in alkylammonium complexes of phosphonate cavitands were studied by mass spectrometric methods and theoretical calculations. The alkylammonium ions included primary, secondary, and tertiary methyl-and ethylammonium ions. Their complexation with mono-, tetra-, and two di-phosphonate cavitands, which differ according to the number and position of H-bond acceptor P ϭ O groups, was evaluated by using different competition experiments, energy-resolved CID, gas-phase H/D-exchange, and ligand-exchange reactions, together with ab initio theoretical optimization of the complexes. The phosphonate cavitands with two or more adjacent P ϭ O groups were found to be selective towards secondary alkylammonium ions, due to simultaneous formation of two stable hydrogen bonds. In the ion-molecule reactions (both H/D-and ligand-exchange), the formation of two stable hydrogen bonds was observed either to slow down the reaction or to completely prevent it. This was, however, limited to situations where two hydrogen bonds are formed between the H-bond donor sites of the alkyl ammonium ion and the vicinal H-bond acceptor sites of the cavitand. (J Am Soc Mass Spectrom 2010, 21, 440 -450)

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Highly Selective Monomethylation of Primary Amines Through Host−Guest Product Sequestration

Cited by 68 publications

References 34 publications

Proton-Mediated Chemistry and Catalysis in a Self-Assembled Supramolecular Host

Proton-Mediated Chemistry and Catalysis in a Self-Assembled Supramolecular Host

Kinetic resolution of constitutional isomers controlled by selective protection inside a supramolecular nanocapsule

Hydrogen bonding in phosphonate cavitands: Investigation of host-guest complexes with ammonium salts

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