1,3-Heterocumulene-to-alkyne

Transition structures and energy barriers of the concerted prototypical cycloaddition reaction of 1,3-heterocumulenes (S=C=S, S=C=NR, RN=C=NR, and heteroanalogs) to acetylene resulting in nucleophilic carbenes were calculated by G2(MP2) and CBS-Q ab initio quantum chemical and by density functional theory (DFT) methods. According to the calculations the activation energies (activation enthalpies) of the homoheteroatomic cumulenes decrease in the order O > S > Se and NH > PH and the reaction energies in the order O > S approximately Se and PH > NH. The reaction of carbon disulfide and acetylene has a lower reaction barrier than that of carbodiimide and acetylene although the first reaction is less exothermic than the second one. The stronger cyclic stabilization of the 1, 3-dithiol-2-ylidene in the transition state is discussed in terms of deformation and stabilization energies and of bond indices. The known reactions of carbon disulfide with ring-strained cycloheptynes were examined by DFT and by DFT:PM3 two-layered hybrid ONIOM methods. In agreement with qualitative experimental findings the activation energy increases and the reaction energy decreases in the sequence S, SO(2), and SiMe(2) if CH(2) in the 5-position of 3,3,7, 7-tetramethyl-1-cycloheptyne is replaced by a heteroatom or heteroatomic group, respectively. The results of these calculations were corroborated by experimental studies with carbon diselenide and isothiocyanates as 1,3-heterocumulenes. The cycloaddition of carbon diselenide to cyclooctyne proceeded faster than with carbon disulfide, the main product being the 1,3-diselenol-2-selone. Under more drastic conditions it was possible to add methyl and phenyl isothiocyanate, respectively, to 3,3,6, 6-tetramethyl-1-thia-4-cycloheptyne. The products are 1:3 adducts (cycloalkyne:isothiocyanate) whose formation is explained by a trapping reaction of the first formed 1,3-thiazol-2-ylidenes.     

2+3] Cycloaddition of ethylene to transition metal oxo compounds. analysis of density functional results by marcus theory.

Density functional results on the [2+3] cycloaddition of ethylene to various transition metal complexes MO(3)(q) and LMO(3)(q) (q = -1, 0, 1) with M = Mo, W, Mn, Tc, Re, and Os and various ligands L = Cp, CH(3), Cl, and O show that the corresponding activation barriers DeltaE(double dagger) depend in quadratic fashion on the reaction energies DeltaE(0) as predicted by Marcus theory. A thermoneutral reaction is characterized by the intrinsic reaction barrier DeltaE(0) of 25.1 kcal/mol. Both ethylene [2+3] cycloaddition to an oxo complex and the corresponding homolytic M-O bond dissociation are controlled by the reducibility of the transition metal center. Indeed, from the easily calculated M-O bond dissociation energy of the oxo complex one can predict the reaction energy DeltaE(0) and hence, by Marcus theory, the corresponding activation barrier DeltaE. This allows a systematic representation of more than 25 barriers of [2+3] cycloaddition reactions that range from 5 to 70 kcal/mol.     

Combining aminocyanine dyes with polyamide dendrons: a promising strategy for imaging in the near-infrared region

Cyanine dyes are known for their fluorescence in the near-IR (NIR) region, which is desirable for biological applications. We report the synthesis of a series of aminocyanine dyes containing terminal functional groups such as acid, azide, and cyclooctyne groups for further functionalization through, for example, click chemistry. These aminocyanine dyes can be attached to polyfunctional dendrons by copper-catalyzed azide alkyne cycloaddition (CuAAC), strain-promoted azide alkyne cycloaddition (SPAAC), peptide coupling, or direct S(NR)1 reactions. The resulting dendron-dye conjugates were obtained in high yields and displayed high chemical stability and photostability. The optical properties of the new compounds were studied by UV/Vis and fluorescence spectroscopy. All compounds show large Stokes shifts and strong fluorescence in the NIR region with high quantum yields, which are optimal properties for in vivo optical imaging.     

Effect of Azide Position on the Rate of Azido Glucose–Cyclooctyne Cycloaddition

The strain-promoted azide–alkyne cycloaddition (SPAAC) is the most widely used bioorthogonal reaction for imaging azide-labeled glycans in living systems. Rapid SPAAC reactions are essential for visualizing biological processes that occur on a short timescale, and efforts to increase SPAAC reaction rates by modulating the cyclooctyne structure have been highly successful. However, optimizing azido sugar structure for improved SPAAC rates has not been explored. In this study, we show that altering azide position on the sugar ring can have a modest but significant impact on SPAAC reaction rate, which has implications for designing and interpreting experiments involving azide-specific bioorthogonal reactions.     

Strain‐Promoted Azide–Alkyne Cycloaddition with Ruthenium(II)–Azido Complexes

The reactivity of an exemplary ruthenium(II)–azido complex towards non‐activated, electron‐deficient, and towards strain‐activated alkynes at room temperature and low millimolar azide and alkyne concentrations has been investigated. Non‐activated terminal and internal alkynes failed to react under such conditions, even under copper(I) catalysis conditions. In contrast, as expected, rapid cycloaddition was observed with electron‐deficient dimethyl acetylenedicarboxylate (DMAD) as the dipolarophile. Since DMAD and related propargylic esters are excellent Michael acceptors and thus unsuitable for biological applications, we investigated the reactivity of the azido complex towards cycloaddition with derivatives of cyclooctyne (OCT), bicyclo[6.1.0]non‐4‐yne (BCN), and azadibenzocyclooctyne (ADIBO). While no reaction could be observed in the case of the less strained cyclooctyne OCT, the highly strained cyclooctynes BCN and ADIBO readily reacted with the azido complex, providing the corresponding stable triazolato complexes, which were amenable to purification by conventional silica gel column chromatography. An X‐ray crystal structure of an ADIBO cycloadduct was obtained and verified that the formed 1,2,3‐triazolato ligand coordinates the metal center through the central N2 atom. Importantly, the determined second‐order rate constant for the ADIBO cycloaddition with the azido complex (k₂=6.9 × 10^?2 M ^?1 s^?1) is comparable to the rate determined for the ADIBO cycloaddition with organic benzyl azide (k₂=4.0 × 10^?1 M ^?1 s^?1). Our results demonstrate that it is possible to transfer the concept of strain‐promoted azide–alkyne cycloaddition (SPAAC) from purely organic azides to metal‐coordinated azido ligands. The favorable reaction kinetics for the ADIBO‐azido‐ligand cycloaddition and the well‐proven bioorthogonality of strain‐activated alkynes should pave the way for applications in living biological systems.     

Structural Distortion of Cycloalkynes Influences Cycloaddition Rates both by Strain and Interaction Energies

The reactivities of 2-butyne, cycloheptyne, cyclooctyne, and cyclononyne in the 1,3-dipolar cycloaddition reaction with methyl azide were evaluated through DFT calculations at the M06-2X/6-311++G(d)//M06-2X/6-31+G(d) level of theory. Computed activation free energies for the cycloadditions of cycloalkynes are 16.5–22.0 kcal mol⁻¹ lower in energy than that of the acyclic 2-butyne. The strained or predistorted nature of cycloalkynes is often solely used to rationalize this significant rate enhancement. Our distortion/interaction–activation strain analysis has been revealed that the degree of geometrical predistortion of the cycloalkyne ground-state geometries acts to enhance reactivity compared with that of acyclic alkynes through three distinct mechanisms, not only due to (i) a reduced strain or distortion energy, but also to (ii) a smaller HOMO–LUMO gap, and (iii) an enhanced orbital overlap, which both contribute to more stabilizing orbital interactions.     

Cyclobis(paraquat-p-phenylene)-based [2]catenanes prepared by kinetically controlled reactions involving alkynes

[reaction: see text] Charged donor-acceptor [2]catenanes, in which the pi-accepting cyclobis(paraquat-p-phenylene) acts as a tetracationic template for the threading-followed-by-clipping of acyclic oligoethers, incorporating centrally a pi-donating 1,5-dioxynaphthalene ring system and terminated either by acetylene units or by acetylene and azide functions, are the products of copper-mediated Eglinton coupling and Huisgen 1,3-dipolar cycloaddition, respectively.     

Reactivity of biarylazacyclooctynones in copper-free click chemistry

The 1,3-dipolar cycloaddition of cyclooctynes with azides, also called "copper-free click chemistry", is a bioorthogonal reaction with widespread applications in biological discovery. The kinetics of this reaction are of paramount importance for studies of dynamic processes, particularly in living subjects. Here we performed a systematic analysis of the effects of strain and electronics on the reactivity of cyclooctynes with azides through both experimental measurements and computational studies using a density functional theory (DFT) distortion/interaction transition state model. In particular, we focused on biarylazacyclooctynone (BARAC) because it reacts with azides faster than any other reported cyclooctyne and its modular synthesis facilitated rapid access to analogues. We found that substituents on BARAC's aryl rings can alter the calculated transition state interaction energy of the cycloaddition through electronic effects or the calculated distortion energy through steric effects. Experimental data confirmed that electronic perturbation of BARAC's aryl rings has a modest effect on reaction rate, whereas steric hindrance in the transition state can significantly retard the reaction. Drawing on these results, we analyzed the relationship between alkyne bond angles, which we determined using X-ray crystallography, and reactivity, quantified by experimental second-order rate constants, for a range of cyclooctynes. Our results suggest a correlation between decreased alkyne bond angle and increased cyclooctyne reactivity. Finally, we obtained structural and computational data that revealed the relationship between the conformation of BARAC's central lactam and compound reactivity. Collectively, these results indicate that the distortion/interaction model combined with bond angle analysis will enable predictions of cyclooctyne reactivity and the rational design of new reagents for copper-free click chemistry.     

Reversible modification of oligodeoxynucleotides: click reaction at phosphate group and alkali treatment

We characterized click reaction between oligodeoxynucleotides (ODNs) possessing acetylene groups at the phosphate unit and azide compounds. Cu(I)-catalyzed cycloaddition proceeded efficiently to form the corresponding functional ODNs. The resulting ODNs could be converted into ordinary ODNs by treatment with aqueous methylamine. The present method successfully achieved a reversible modification of ODNs.     

A computational study of chlorocarbene additions to cyclooctyne

Dichloro- and phenylchlorocarbene (CCl2 and PhCCl) add to cyclooctyne via a barrierless process (MP2/6-311+G*, B3LYP/6-311+G*, B3LYP/6-31G*) to yield the expected corresponding cyclopropene adducts. A three-dimensional potential energy surface (PES) for CCl2 addition to cyclooctyne (B3LYP/6-31G*) shows the formation of the cyclopropene product and also possible formation of a vinylcarbene. Residing in a shallow energy well, the vinylcarbene easily rearranges to the cyclopropene product, or to an exocyclic vinyl bicyclo[3.3.0]octane. Although the calculated three-dimensional PES indicates possible dynamic control of the cyclooctyne-chlorocarbene system through the putative formation of a vinylcarbene (in addition to the expected cyclopropene), additional calculations and preliminary experimental work show paths through the vinylcarbene to be unlikely. If the additions of chlorocarbenes to cyclooctyne are controlled by reaction dynamics, we predict that the vast majority of the reactions proceed via traditional carbene cycloaddition with only a very minor amount of products formed from the alternative pathway.     

Isolable tris(alkyne) and bis(alkyne) complexes of gold(I)

Golden trefoils: Tris(alkyne)gold complex [(coct)(3)Au][SbF(6)] (see picture; 1-SbF(6)) can be synthesized from cyclooctyne (coct) and AuSbF(6) generated in situ. Treatment of AuCl with cyclooctyne led to the bis(alkyne)gold complex [Au(coct)(2)Cl] (2). DFT analysis indicates that the cyclooctyne ligands are net electron donors in 1 but overall electron acceptors in 2. AuSbF(6) is shown to mediate [2+2+2] cycloaddition reactions of alkynes.     

A potent and highly selective inhibitor of human alpha-1,3-fucosyltransferase via click chemistry

Potent inhibitors of fucosyltransferases, and glycosyltransferases in general, have been elusive due to the inherent barriers surrounding the family of glycosyltransfer reactions. The problems of weak substrate affinity and low catalytic proficiency of fucosyltransferase was offset by recruiting additional binding features, in this case hydrophobic interactions, to produce a high affinity inhibitor, 24, with Ki = 62 nM. The molecule was identified from a GDP-triazole library of 85 compounds, which was produced by the Cu(I)-catalyzed [2 + 3] cycloaddition reaction between azide and acetylene reactants, followed by in situ screening without product isolation.     

Vitamin D side chain triazole analogs via cycloaddition `click' chemistry

Cycloaddition of a vitamin D side chain terminal acetylene with phenyl azide and separately with a vitamin D side chain terminal azide produced the corresponding 1,2,3-triazole monomeric and dimeric analogs of 1α-hydroxyvitamin D₃ in good yields.     

A Survey of Strain-Promoted Azide–Alkyne Cycloaddition in Polymer Chemistry

Highly efficient reactions that enable the assembly of molecules into complex structures have driven extensive progress in synthetic chemistry. In particular, reactions that occur under mild conditions and in benign solvents, while producing no by-products and rapidly reach completion are attracting significant attention. Amongst these, the strain-promoted azide–alkyne cycloaddition, involving various cyclooctyne derivatives reacting with azide-bearing molecules, has gained extensive popularity in organic synthesis and bioorthogonal chemistry. This reaction has also recently gained momentum in polymer chemistry, where it has been used to decorate, link, crosslink, and even prepare polymer chains. This survey highlights key achievements in the use of this reaction to produce a variety of polymeric constructs for disparate applications.     

Theoretical studies on the role of pi-electron delocalization in determining the conformation of N-benzylideneaniline with three types of LMO basis sets

To understand the role of pi-electron delocalization in determining the conformation of the NBA (Ph-N==CH-Ph) molecule, the following three LMO (localized molecular orbital) basis sets are constructed: a LFMO (highly localized fragment molecular orbital), an NBO (natural bond orbital), and a special NBO (NBO-II) basis sets, and their localization degrees are evaluated with our suggesting index D(L). Afterward, the vertical resonance energy DeltaE(V) is obtained from the Morokuma's energy partition over each of three LMO basis sets. DeltaE(V) = DeltaE(H) (one electron energy) + DeltaE(two) (two electron energy), and DeltaE(two) = DeltaE(Cou) (Coulomb) + DeltaE(ex) (exchange) + DeltaE(ec) (or SigmaDeltaE(n)) (electron correction). DeltaE(H) is always stabilizing, and DeltaE(Cou) is destabilizing for all time. In the case of the LFMO basis set, DeltaE(Cou) is so great that DeltaE(two) > |DeltaE(H)|. Therefore, DeltaE(V) is always destabilizing, and is least destabilizing at about the theta = 90 degrees geometry. Of the three calculation methods such as HF, DFT, and MPn (n = 2, 3, and 4), the MPn method provides DeltaE(V) with the greatest value. In the case of the NBO basis set, on the contrary, DeltaE(V) is stabilizing due to DeltaE(Cou) being less destabilizing, and it is most stabilizing at a planar geometry. The LFMO basis set has the highest localization degree, and it is most appropriate for the energy partition. In the NBA molecule, pi-electron delocalization is destabilization, and it has a tendency to distort the NBA molecular away from its planar geometry as far as possible.     

Synthesis of 1-phenyl-2,2-difluoro-3,3-bis(trifluoromethyl)aziridine

Conclusions 1-Phenyl-2,2-difluoro-3,3-bis(trifluoromethyl)aziridine was obtained by the cycloaddition of difluorocarbene to hexafluoroacetone anil or by the reaction of octafluoroisobutylene with phenyl azide.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 1, pp. 248–249, January, 1986.     

3-nitro- and 3-bromo-3-nitroacrylates in reactions with phenyl azide

1,3-Dipolar cycloaddition of alkyl 3-nitro-and 3-bromo-3-nitroacrylates to phenyl azide gives regioisomeric alkyl 5(4)-nitro-1-phenyl-4,5-dihydro-1H-1,2,3-triazole-4(5)-carboxylates, the corresponding triazoles both with and without nitro group, and alkyl 3-nitro-1-phenylaziridine-2-carboxylates. Nitrotriazolecarboxylates were found to lose the ester moiety during chromatographic separation of the products on aluminum oxide. The structure of the products was determined on the basis of IR, ¹H NMR, and X-ray diffraction data.     

Addition d'azides a des olefines trisubstituees par des groupements electroattracteurs

The reaction of benzyl, methyl and phenyl azide, with olefins substituted by three electron-withdrawing groups, has been studied. This reaction gives in certain cases only one triazoline (single orientation of the cycloaddition). In other cases, a mixture of a triazoline and a diazocompound (double orientation of the cycloaddition) is obtained. The structure assignment of the triazolines is confirmed using chemical methods and 13C-NMR. Thermally, diazocompounds rearrange to enaminoesters which cyclise at high temperature to quinolines.     

Well‐controlled polymerization of 2‐azidoethyl methacrylate at near room temperature and click functionalization

A functional monomer with a pendant azide moiety, 2‐azidoethyl methacrylate (AzMA), was polymerized via reversible addition‐fragmentation chain transfer (RAFT) polymerization with excellent control over the molecular weight distribution (PDI = 1.05–1.15). The subsequent copper‐catalyzed Huisgen 1,3‐dipolar cycloadditions of phenyl acetylene with polyAzMA was achieved at room temperature with high conversion. The resulting functional polymer exhibited identical ¹H NMR and IR spectra with the polymer of the same molecular structure but prepared by a prefunctionalization approach, confirming the retention of the azide side chains during the RAFT polymerization of AzMA. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 4300–4308, 2007