The Huisgen 1,3-dipolar cycloaddition reaction of organic azides and alkynes has gained considerable attention in recent years due to the introduction in 2001 of Cu(1) catalysis by Tornoe and Meldal, leading to a major improvement in both rate and regioselectivity of the reaction, as realized independently by the Meldal and the Sharpless laboratories. The great success of the Cu(1) catalyzed reaction is rooted in the fact that it is a virtually quantitative, very robust, insensitive, general, and orthogonal ligation reaction, suitable for even biomolecular ligation and in vivo tagging or as a polymerization reaction for synthesis of long linear polymers. The triazole formed is essentially chemically inert to reactive conditions, e.g. oxidation, reduction, and hydrolysis, and has an intermediate polarity with a dipolar moment of ∼5 D. The basis for the unique properties and rate enhancement for triazole formation under Cu(1) catalysis should be found in the high ∆G of the reaction in combination with the low character of polarity of the dipole of the noncatalyzed thermal reaction, which leads to a considerable activation barrier. In order to understand the reaction in detail, it therefore seems important to spend a moment to consider the structural and mechanistic aspects of the catalysis. The reaction is quite insensitive to reaction conditions as long as Cu(1) is present and may be performed in an aqueous or organic environment both in solution and on solid support.

Cu-catalyzed azide-alkyne cycloaddition.

The study of biomolecules in their native environments is a challenging task because of the vast complexity of cellular systems. Technologies developed in the last few years for the selective modification of biological species in living systems have yielded new insights into cellular processes. Key to these new techniques are bioorthogonal chemical reactions, whose components must react rapidly and selectively with each other under physiological conditions in the presence of the plethora of functionality necessary to sustain life. Herein we describe the bioorthogonal chemical reactions developed to date and how they can be used to study biomolecules.

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Bioorthogonal Chemistry: Fishing for Selectivity in a Sea of Functionality

▪ Abstract Proton-coupled electron transfer (PCET) is an important mechanism for charge transfer in a wide variety of systems including biology- and materials-oriented venues. We review several are...

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Proton-Coupled Electron Transfer

Since the discovery of organic azides by Peter Griess more than 140 years ago, numerous syntheses of these energy-rich molecules have been developed. In more recent times in particular, completely new perspectives have been developed for their use in peptide chemistry, combinatorial chemistry, and heterocyclic synthesis. Organic azides have assumed an important position at the interface between chemistry, biology, medicine, and materials science. In this Review, the fundamental characteristics of azide chemistry and current developments are presented. The focus will be placed on cycloadditions (Huisgen reaction), aza ylide chemistry, and the synthesis of heterocycles. Further reactions such as the aza-Wittig reaction, the Sundberg rearrangement, the Staudinger ligation, the Boyer and Boyer-Aube rearrangements, the Curtius rearrangement, the Schmidt rearrangement, and the Hemetsberger rearrangement bear witness to the versatility of modern azide chemistry.

Organic Azides: An Exploding Diversity of a Unique Class of Compounds

Copper-catalyzed azide–alkyne cycloaddition (CuAAC) is a widely utilized, reliable, and straightforward way for making covalent connections between building blocks containing various functional groups. It has been used in organic synthesis, medicinal chemistry, surface and polymer chemistry, and bioconjugation applications. Despite the apparent simplicity of the reaction, its mechanism involves multiple reversible steps involving coordination complexes of copper(I) acetylides of varying nuclearity. Understanding and controlling these equilibria is of paramount importance for channeling the reaction into the productive catalytic cycle. This tutorial review examines the history of the development of the CuAAC reaction, its key mechanistic aspects, and highlights the features that make it useful to practitioners in different fields of chemical science.

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Copper-catalyzed azide–alkyne cycloaddition (CuAAC) and beyond: new reactivity of copper(I) acetylides

Huisgen's 1,3-dipolar cycloadditions become nonconcerted when copper(I) acetylides react with azides and nitrile oxides, providing ready access to 1,4-disubstituted 1,2,3-triazoles and 3,4-disubstituted isoxazoles, respectively. The process is highly reliable and exhibits an unusually wide scope with respect to both components. Computational studies revealed a stepwise mechanism involving unprecedented metallacycle intermediates, which appear to be common for a variety of dipoles.

Copper(I)-catalyzed synthesis of azoles. DFT study predicts unprecedented reactivity and intermediates.

The catalytic reaction pathways in enzymes synthetic systems were investigated. In this regard, the electron transfer, proton transfer, and charge flow to energetics and structural transformations were discussed. The quantum chemical studies of the reaction mechanisms of the metalloenzymes revealed the intermediates and transition states for the enzymes. The mechanisms of protein tyrosine phosphatases (PTPases) and hammerhead ribozyme chemistry were also presented.

Quantum chemical studies of intermediates and reaction pathways in selected enzymes and catalytic synthetic systems.

Density functional theory geometry optimizations and reduction potential calculations are reported for all five known oxidation states of [Fe4S4(SCH3)4]n- (n = 0, 1, 2, 3, 4) clusters that form the active sites of iron−sulfur proteins. The geometry-optimized structures tend to be slightly expanded relative to experiment, with the best comparison found in the [Fe4S4(SCH3)4]2- model cluster, having bond lengths 0.03 A longer on average than experimentally observed. Environmental effects are modeled with a continuum dielectric, allowing the solvent contribution to the reduction potential to be calculated. The calculated protein plus solvent effects on the reduction potentials of seven proteins (including high potential iron proteins, ferredoxins, the iron protein of nitrogenase, and the “X”, “A”, and “B” centers of photosystem I) are also examined. A good correlation between predicted and measured absolute reduction potentials for each oxidation state of the cluster is found, both for relative potentials wit...

Density Functional and Reduction Potential Calculations of Fe4S4 Clusters

The MN S = 3/2 resting state of the FeMo cofactor of nitrogenase has been proposed to have metal-ion valencies of either Mo4+6Fe2+Fe3+ (derived from metal hyperfine interactions) or Mo4+4Fe2+3Fe3+ (from Mossbauer isomer shifts). Spin-polarized broken-symmetry (BS) density functional theory (DFT) calculations have been undertaken to determine which oxidation level best represents the MN state and to provide a framework for understanding its energetics and spectroscopy. For the Mo4+6Fe2+Fe3+ oxidation state, the spin coupling pattern for several spin state alignments compatible with S = 3/2 were generated and assessed by energy and geometric criteria. The most likely BS spin state is composed of a Mo3Fe cluster with spin Sa = 2 antiferromagnetically coupled to a 4Fe‘ cluster with spin Sb = 7/2. This state has a low DFT energy for the isolated FeMoco cluster and the lowest energy when the interaction with the protein and solvent environment is included. This spin state also displays calculated metal hyperfin...

FeMo Cofactor of Nitrogenase: A Density Functional Study of States MN, MOX, MR, and MI

Broken symmetry density functional and electrostatics calculations have been used to shed light on which of three proposed atoms, C, N, or O, is most likely to be present in the center of the FeMoco, the active site of nitrogenase. At the Mo4+4Fe2+3Fe3+ oxidation level, a central N3- anion results in (1) calculated Fe−N bond distances that are in very good agreement with the recent high-resolution X-ray data of Einsle et al.; (2) a calculated redox potential of 0.19 eV versus the standard hydrogen electrode (SHE) for FeMoco(oxidized) + e- → FeMoco(resting), in good agreement with the measured value of −0.042 V in Azotobacter vinelandii; and (3) average Mossbauer isomer shift values (ISav = 0.48 mm s-1) compatible with experiment (ISav = 0.40 mm s-1). At the more reduced Mo4+6Fe2+1Fe3+ level, the calculated geometry around a central N3- anion still correlates well with the X-ray data, but the average Mossbauer isomer shift value (ISav = 0.54 mm s-1) and the redox potential of −2.21 eV show a much poorer ag...

Timothy Lovell

Papers

Copper(I)-catalyzed synthesis of azoles. DFT study predicts unprecedented reactivity and intermediates.

Quantum chemical studies of intermediates and reaction pathways in selected enzymes and catalytic synthetic systems.

Density Functional and Reduction Potential Calculations of Fe4S4 Clusters

FeMo Cofactor of Nitrogenase: A Density Functional Study of States MN, MOX, MR, and MI

Structural, spectroscopic, and redox consequences of a central ligand in the FeMoco of nitrogenase: a density functional theoretical study.