The ribosome builds proteins by joining together amino acids in an order determined by messenger RNA. Here, we report on the design, synthesis, and operation of an artificial small-molecule machine that travels along a molecular strand, picking up amino acids that block its path, to synthesize a peptide in a sequence-specific manner. The chemical structure is based on a rotaxane, a molecular ring threaded onto a molecular axle. The ring carries a thiolate group that iteratively removes amino acids in order from the strand and transfers them to a peptide-elongation site through native chemical ligation. The synthesis is demonstrated with ~10(18) molecular machines acting in parallel; this process generates milligram quantities of a peptide with a single sequence confirmed by tandem mass spectrometry.

Mechanical force, with its ability to distort, bend, and stretch chemical bonds, is unique in the way it activates chemical reactions. In polymer mechanochemistry, the force is transduced in a directional fashion, and the efficiency of activation depends on how well the force is transduced from the polymer to the scissile bond in the mechanophore (i.e., mechanochemical coupling). We have investigated the effects of regio- and stereochemistry on the rate of force-accelerated retro-Diels-Alder reactions of furan/maleimide adducts. Four adducts, presenting an endo or exo configuration and proximal or distal geometry, were activated in solution by ultrasound-generated elongational forces. A combination of structural (H NMR) and computational (CoGEF) analyses allowed us to interrogate the mechanochemical activation of these adducts. We found that, unlike its thermal counterpart where the reactivity is dictated by the stereochemistry, the mechanical reactivity is mainly dependent on the regiochemistry. Remarkably, the thermally active distal-exo adduct becomes inert under tension due to poor mechanochemical coupling.

We report on an improved strategy for the preparation of artificial molecular machines that can pick up and assemble reactive groups in sequence by traveling along a track. In the new approach a preformed rotaxane synthon is attached to the end of an otherwise fully formed strand of building blocks. This "rotaxane-capping" protocol is significantly more efficient than the "final-step-threading" method employed previously and enables the synthesis of threaded molecular machines that operate on extended oligomer, and potentially polymer, tracks. The methodology is exemplified through the preparation of a machine that adds four amino acid building blocks from a strand in sequence, featuring up to 20-membered ring native chemical ligation transition states.

Strong and stable under tension?

Chemical reactions usually proceed through radical, concerted, or ionic mechanisms, yet transformations in which these three mechanisms take place at the same time are rare. In polymer mechanochemistry a mechanical force, transduced along polymer chains, is used to activate covalent bonds in mechanosensitive molecules (mechanophores). Cleavage of a C-C bond often follows a homolytic pathway but some mechanophores have also been designed that react in a concerted or, more rarely, a heterolytic manner. Here, using 1 H-and 19 F-nuclear magnetic resonance spectroscopy in combination with deuterium labelling, we show that the dissociation of a mechanophore built around an Nheterocyclic carbene precursor proceeds with the rupture of a C-C bond through concomitant heterolytic, concerted, and homolytic pathways. The distribution of products likely arises from a posttransition-state bifurcation in the reaction pathway, and their relative proportion is dictated by the polarisation of the scissile C-C bond.Mechanical scission of covalent bonds usually occurs in a homolytic fashion 1,2 although mechanophores can be designed to react in a concerted 3 or, more rarely, heterolytic fashion [4][5][6][7][8][9][10] . Perhaps the most interesting aspect of polymer mechanochemistry comes from the fact that molecules under tension follow reaction pathways that can significantly deviate from their zero-force mechanism and lead to unexpected outcomes 2 . This deviation can be expressed in the nature of the product formed, such as in the electrocyclic ring openings of strained cycles along a symmetry forbidden pathway, 11 12 and/or in the nature of the reactive intermediates 13,14 , or even in the change of the rate-determining step itself 15,16 17 .Here we show that the ultrasound-induced dissociation of a neutral N-heterocyclic carbene precursor proceeds with the rupture of a single C-C bond via concomitant heterolytic, concerted, and homolytic dissociation pathways.

The activation mode of a rotaxane-based organocatalyst with both secondary amine and squaramide catalytic units can be switched with acid or base, affording different products from a mixture of three building blocks.

Biomolecular machines perform types of complex molecular-level tasks that artificial molecular machines can aspire to. The ribosome, for example, translates information from the polymer track it traverses (messenger RNA) to the new polymer it constructs (a polypeptide) . The sequence and number of codons read determines the sequence and number of building blocks incorporated into the biomachine-synthesized polymer. However, neither control of sequence nor the transfer of length information from one polymer to another (which to date has only been accomplished in man-made systems through template synthesis) is easily achieved in the synthesis of artificial macromolecules. Rotaxane-based molecular machines have been developed that successively add amino acids (including β-amino acids ) to a growing peptide chain by the action of a macrocycle moving along a mono-dispersed oligomeric track derivatized with amino-acid phenol esters. The threaded macrocycle picks up groups that block its path and links them through successive native chemical ligation reactions to form a peptide sequence corresponding to the order of the building blocks on the track. Here, we show that as an alternative to translating sequence information, a rotaxane molecular machine can transfer the narrow polydispersity of a leucine-ester-derivatized polystyrene chain synthesized by atom transfer radical polymerization to a molecular-machine-made homo-leucine oligomer. The resulting narrow-molecular-weight oligomer folds to an α-helical secondary structure that acts as an asymmetric catalyst for the Juliá-Colonna epoxidation of chalcones.

The hydrosilylation of terminal alkynes by silanes catalyzed by N-heterocyclic carbene platinum(0) complexes has been investigated. The alkynes included 1-octyne and phenylacetylene. The silanes investigated were bis(trimethylsilyloxy)methylsilane, (trimethylsilyloxy)dimethylsilane, tert-butyldimethylsilane, triphenylsilane, phenyldimethylsilane, triethylsilane, and triethoxysilane. X-ray crystal structures for [Pt(N,N‘-dicyclohexylimidazol-2-ylidene)(η2-dimethylacetylenedicarboxylate)2] (8) and [Pt{C(E)C(E)−C(E)C(E)}(N,N‘-dimethylbenzimidazol-2-ylidene)(σ-NCCH3)] (10) (E = CO2Me) have been obtained. A selectivity model, based on structural parameters of the N-heterocyclic carbene, has been devised in order to rationalize the observed regioselectivity obtained. By a judicious choice of catalyst, alkyne, and silane, the regioselectivity of the addition can be controlled.