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 halogen bond occurs when there is evidence of a net attractive interaction between an electrophilic region associated with a halogen atom in a molecular entity and a nucleophilic region in another, or the same, molecular entity. In this fairly extensive review, after a brief history of the interaction, we will provide the reader with a snapshot of where the research on the halogen bond is now, and, perhaps, where it is going. The specific advantages brought up by a design based on the use of the halogen bond will be demonstrated in quite different fields spanning from material sciences to biomolecular recognition and drug design.

The Halogen Bond

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

Design strategies for water-soluble small molecular chromogenic and fluorogenic probes.

DNA is increasingly being used as the engineering material of choice for the construction of nanoscale circuits, structures, and motors. Many of these enzyme-free constructions function by DNA strand displacement reactions. The kinetics of strand displacement can be modulated by toeholds, short single-stranded segments of DNA that colocalize reactant DNA molecules. Recently, the toehold exchange process was introduced as a method for designing fast and reversible strand displacement reactions. Here, we characterize the kinetics of DNA toehold exchange and model it as a three-step process. This model is simple and quantitatively predicts the kinetics of 85 different strand displacement reactions from the DNA sequences. Furthermore, we use toehold exchange to construct a simple catalytic reaction. This work improves the understanding of the kinetics of nucleic acid reactions and will be useful in the rational design of dynamic DNA and RNA circuits and nanodevices.

http://nablab.rice.edu/publications/JACS2009.pdf

Control of DNA Strand Displacement Kinetics Using Toehold Exchange

o-(Pyrrolidinylmethyl)phenylboronic acid (4) and its complexes with bifunctional substrates such as catechol, alpha-hydroxyisobutyric acid, and hydrobenzoin have been studied in detail by X-ray crystallography, (11)B NMR, and computational analysis. The N-B interactions in analogous boronic acids and esters have been extensively cited in molecular recognition and chemosensing literature. The focal point of this study was to determine the factors that are pertinent to the formation of an intramolecular N-B dative bond. Our structural study predicts that the formation of an N-B dative bond, and/or solvent insertion to afford a tetrahedral boronate anion, depends on the solvent and the complexing substrate present. Specifically, from (11)B NMR studies, complexation of 4 with electron-withdrawing and/or vicinally bifunctionalized substrates promotes both the formation of N-B dative bonds and the solvation of sp(2) boron to a tetrahedral sp(3) boronate. In the solid state, the presence of an N-B dative bond in the complex of 4 and catechol (7) depends on the solvent from which it crystallizes. From chloroform, an N-B bond was observed, whereas from methanol, a methoxylated boronate was formed, where the methoxy group is hydrogen-bonded with the neighboring tertiary ammonium ion. The structural optimization of compounds 4 and 7 using density functional theory in a simulated water continuum also predicts that complexation of 4 and catechol promotes either the formation of an N-B bond or solvolysis if 1 equiv of water is present. The conclusion from this study will help in the design of future chemosensing technologies based on o-(N,N-dialkylaminomethyl)arylboronate scaffolds that are targeting physiologically important substances such as saccharides, alpha-hydroxycarboxylates, and catecholamines.

A structural investigation of the N-B interaction in an o-(N,N-dialkylaminomethyl)arylboronate system

An enantioselective indicator-displacement assay was developed to determine enantiomeric excess (ee) and concentration of α-hydroxyacid samples with two independent absorption measurements. The inherent relationship between the absorbance of the indicator-displacement ensemble and the overall concentration and ee of the analyte was established through solution equilibria.

Facile Quantification of Enantiomeric Excess and Concentration with Indicator-Displacement Assays: An Example in the Analyses of α-Hydroxyacids

Apparent copper(II)-accelerated azide-alkyne cycloaddition.

Highly Sensitive Fluorescent Probes for Zinc Ion Based on Triazolyl-Containing Tetradentate Coordination Motifs

Enantioselective association events between boronic acid receptors and bifunctional substrates such as α-hydroxycarboxylates and vicinal diols were exploited to develop enantioselective indicator-displacement assays. It was found that the sensitivity of the assay could be tuned by using either colorimetric or fluorescent indicators. Mathematical principles were established for concurrent determination of concentration and enantiomeric excess (ee) of a chiral analyte, which has been a challenge to the high-throughput analysis of chiral samples. Furthermore, experimental protocols were optimized to maximize the chiral resolution of the assay and to improve the accuracy of the ee measurements.

Lei Zhu

Papers

A structural investigation of the N-B interaction in an o-(N,N-dialkylaminomethyl)arylboronate system

Facile Quantification of Enantiomeric Excess and Concentration with Indicator-Displacement Assays: An Example in the Analyses of α-Hydroxyacids

Apparent copper(II)-accelerated azide-alkyne cycloaddition.

Highly Sensitive Fluorescent Probes for Zinc Ion Based on Triazolyl-Containing Tetradentate Coordination Motifs

Guidelines in implementing enantioselective indicator-displacement assays for α-hydroxycarboxylates and diols