Donor-acceptor triazenes: synthesis, characterization, and study of their electronic and thermal properties

A new class of 1,3-disubstituted-triazenes were synthesized by coupling functionalized benzimidazol-2-ylidenes, as their free N-heterocyclic carbenes or generated in situ from their respective benzimidazolium precursors, to various aryl azides in modest to excellent isolated yields (36-99%). Electron delocalization between the two coupled components was studied using UV-vis spectroscopy, NMR spectroscopy, and X-ray crystallography. Depending on the complementarity of the functional groups on the N-heterocyclic carbenes and the organic azides, the respective triazenes were found to exhibit lambda(max) values ranging between 364 and 450 nm. X-ray crystallography revealed bond alteration patterns in a series of triazenes characteristic of donor-acceptor compounds. Triazene thermal stabilities were studied using thermogravimetric analysis and found to be strongly dependent on the sterics of the benzimidazol-2-ylidene component and the electronics of the azide component. Triazenes possessing bulky N-substituents (e.g., neo-pentyl, tert-butyl, etc.) were stable in the solid-state to temperatures exceeding 150 degrees C, whereas analogues with small N-substituents (e.g., methyl) were found to slowly decompose at room temperature. Triazenes featuring electron-rich phenyl azide components decomposed at higher temperatures than their electron-deficient analogues. Products of the thermally induced triazene decomposition reaction were identified as molecular nitrogen and the respective guanidine. Using an isotopically labeled triazene, the mechanism of the decomposition reaction was found to be analogous to the Staudinger reaction.     

Novel triazene dyes from N-heterocyclic carbenes and azides: syntheses,stability, and spectroscopic properties

A series of substituted triazene dyes were synthesized by coupling functionalized imidazol-2-ylidenes with various azides (alkyl, vinyl, aryl, and heteroaryl), in moderate to excellent yields. Their structures were confirmed by spectroscopic studies (IR, NMR, UV–vis, and HRMS). Additionally, the solid-state structure of triazene dye 7 was secured by single crystal X-ray diffraction. Electron delocalization between the two coupled components was studied using UV–vis spectroscopy. The respective triazenes were found to exhibit λ_max values ranging between 294 and 450 nm.     

Triazene formation via reaction of imidazol-2-ylidenes with azides

Treatment of N-heterocyclic carbenes (as their free carbenes or generated in situ) with alkyl, aryl, acyl or tosyl azides afforded the respective substituted triazenes in excellent yields.     

Preparation of pyrido[1,2-c][1,2,4]triazole-based π-conjugated triazene as a Fe~(3+) ion fluorescent sensor

A highly efficient coupling reaction of pyrido[1,2-c] [1,2,4]triazole carbene precursors with sulfonyl azides leading to structurally diverse π-conjugated triazenes has been realized under very mild conditions.     

Intermolecular [3 + 3]-cycloadditions of azides with the Nazarov intermediate

Tetrasubstituted 1,4-dien-3-ones undergo Nazarov cyclization at low temperature, followed by reaction with organic azides via an apparent [3 + 3]-cycloaddition to give bridged bicyclic triazenes. These products do not appear to be intermediates in the previously described Schmidt-type process to furnish dihydropyridones. The reaction typically occurs with high diastereoselectivity.     

Preparation of polyfunctional aryl azides from aryl triazenes. A new synthesis of ellipticine, 9-methoxyellipticine, isoellipticine, and 7-carbethoxyisoellipticine

The preparation of polyfunctional aryl azides by the reaction of aryl triazenes with NaN3 in the presence of KHSO4 or BF3.OEt2/TFA (trifluoroacetic acid) has been described. A variety of functional groups (halides, esters, ketones, nitriles, aldehydes, and boronic esters) are tolerated under the Lewis acidic conditions. By using this methodology, the potent antitumor agents, ellipticine and 9-methoxyellipticine, have been synthesized. In addition, isoellipticine and a related derivative, 7-carbethoxyisoellipticine, were also prepared.     

The electronic absorption spectra of some acyl azides molecular orbital treatment

The electronic absorption spectra of benzoyl azide and its derivatives: p-methyl, p-methoxy, p-chloro and p-nitrobenzoyl azide were investigated in different solvents. The observed spectra differ basically from the electronic spectra of aryl azides or alkyl azides. Four intense pi-pi* transitions were observed in the accessible UV region of the spectrum of each of the studied compounds. The contribution of charge transfer configurations to the observed transitions is rather weak. Shift of band maximum with solvent polarity is minute. On the other hand, band intensity is highly dependent on the solvent used. The observed transitions are delocalized rather than localized ones as in the case with aryl and alkyl azides. The attachment of the CO group to the azide group in acyl azides has a significant effect on the electronic structure of the molecule. The arrangements as well as energies of the molecular orbitals are different in acyl azides from those in aryl azides. The first electronic transition in phenyl azide is at 276 nm, whereas that of bezoyle azide is at 251 nm. Ab initio molecular orbital calculations using both RHF/6-311G* and B3LYP/6-31+G* levels were carried out on the ground states of the studied compounds. The wave functions of the excited states were calculated using the CIS and the AM1-CI procedures.     

Synthesis of Firefly Luciferin Analogues and Evaluation of the Luminescent Properties

Five new firefly luciferin ( 1 ) analogues were synthesized and their light emission properties were examined. Modifications of the thiazoline moiety in 1 were employed to produce analogues containing acyclic amino acid side chains ( 2 – 4 ) and heterocyclic rings derived from amino acids ( 5 and 6 ) linked to the benzothiazole moiety. Although methyl esters of all of the synthetic derivatives exhibited chemiluminescence activity, only carboluciferin ( 6 ), possessing a pyrroline‐substituted benzothiazole structure, had bioluminescence (BL) activity (λ_max=547 nm). Results of bioluminescence studies with AMP‐carboluciferin (AMP=adenosine monophosphate) and AMP‐firefly luciferin showed that the nature of the thiazoline mimicking moiety affected the adenylation step of the luciferin–luciferase reaction required for production of potent BL. In addition, BL of 6 in living mice differed from that of 1 in that its luminescence decay rate was slower.     

Photolysis of regioisomeric diazides of 1,2-diphenylacetylenes studies by matrix-isolation spectroscopy and DFT calculations

A series of diazides of 1,2-diphenylacetylenes was photolyzed in matrices at low temperature and transient photoproducts were characterized by using IR, UV/vis methods combined with ESR studies. Theoretical calculations were also used to understand the experimental findings. The introduction of phenylethynyl groups on phenyl azides has little effect on the photochemical pathway. Thus, upon photoexcitation, (phenylethynyl)phenyl azides afforded the corresponding triplet nitrene, which is in photoequilibrium with the corresponding azacycloheptatetraene. In marked contrast, azidophenylethynyl groups exhibited a dramatic effect not only on the photochemical pathway of phenyl azides but also on the electronic and molecular structure of the photoproducts. The patterns of the effect depended upon the relative position of azide groups in the diphenylacetylene unit. Whenever two azide groups were situated in a conjugating position with respect to each other, as in p,p'-, o,o'-, and p,o'-bis(azides), the azides always resulted in the formation of a quinoidal diimine diradical in which unpaired electrons were extensively delocalizedin the pi-conjugation. The situation changed rather dramatically when azide groups were introduced in the meta position. Thus, the formation of azacycloheptatetraene was noted in the photolysis of the m.m'-isomer. ESR studies indicated the generation of a quintet state that was shown to be a thermally populated state with a very small energy gap of ca. 100 cal mol(-1). The m,p'-isomer was shown to be an excellent precursor for the high-spin quintet dinitrene. The IR spectra of the photoproduct showed no bands ascribable to azacycloheptatetraene. The observed spectra were in good agreement with that calculated for the quintet state. Strong EPR signals assignable to the quintet state were observed, along with rather weak signals due to mononitrenes. Moreover, the quintet bis(nitrene) was rather photostable under these conditions.     

Study of luminescence properties of cyclic and acyclic thiadiazole-containing compounds

Luminescence properties of thiadiazole-containing compounds of cyclic and acyclic structure have been investigated. All compounds are characterized by fluorescence in the region 500–600 nm. The highest quantum yield of luminescence in the studied series is exhibited by acyclic product of the ABA type (where A is thiadiazole cycle, B is isoindole cycle) with N-pentylthiadiazoline fragments.     

Zur thermolyse von silyltriazenen

Whilst mono(silyl)triazenes R′N=N---NR′(SiR₃) and organyl triazenes R′N=N---NR′₂ are of comparable thermal stability and decay by a radical reaction, bis(silyl)triazenes R′N=N---N(SiR₃)₂ (R′=aryl, R=Me, Et, OMe) decompose at room temperature in a non-radical reaction to yield amines R′N(SiR₃)₂ and nitrogen. Kinetic investigations of the mechanism of the non-radical thermolysis of triazenes show that the rate of the thermolysis of R′N=N---N(SiR₃)₂ is determined both from an isomerisation equilibrium forming (R₃Si)R′N---N=N(SiR₃) and from the rate of decomposition of this compound to the thermolysis products. Tris(silyl)triazenes, (R₃Si)₂N---N=N(SiR₃), hitherto not synthesized, are expected to be even more unstable than the bis(silyl)triazenes which have been examined by us.     

Base-promoted reactions of bridged ketones and 1,3- and 1,4-haloalkyl azides: competitive alkylation vs azidation reactions of ketone enolates

The reactions of 1,3- and 1,4-haloalkyl azides with enolates of 2-norbornanone (and a ring-expanded analog) afford polycyclic 1,2,3-triazolines in good yields. The reaction occurs by the initial azidation of the ketone enolate, followed in order by triazoline formation and O-alkylation. An interesting element of this process is the preferential reaction of the alkyl azide with an enolate anion as opposed to the more familiar reaction of the alkyl halide (including Cl and I derivatives). Reactions of acyclic or monocyclic enolates generally lead to 1,2,3-triazoles but none of the alternative C-alkylation product.     

Photoinduced C-N bond cleavage in 2-azido-1,3-diphenyl-propan-1-one derivatives: photorelease of hydrazoic acid

Photolysis of 3-azido-1,3-diphenyl-propan-1-one (1a) in toluene yields 1,3-diphenyl-propen-1-one (2), whereas irradiation of 3-azido-2,2-dimethyl-1,3-diphenyl-propan-1-one (1b) results in the formation of mainly 2,2-dimethyl-1,3-diphenyl-propan-1-one. Laser flash photolysis (308 nm) of 1a,b in acetonitrile reveals a transient absorption (lambda max = approximately 310 nm) due to the formation of radicals 4a and 4b, respectively, which have lifetimes of approximately 14 micros at ambient temperature. TD-DFT calculations (B3LYP/6-31+G(d)) reveal that the first and second excited states of the triplet ketone (T1K (n,pi*) and T2K (pi,pi*)) in azide 1a are almost degenerate, at approximately 74 and 76 kcal/mol above the ground state (S0), respectively. Similarly, azide 1b has T1K and T2K 75 and 82 kcal/mol above S0, respectively. The calculated transition state for cleaving the C-N bond is located 71 and 74 kcal/mol above S0 in azides 1a and 1b, respectively. The calculated bond dissociation energies for breaking the C-N bond are 55 and 58 kcal/mol for azides 1a and 1b, respectively, making C-N bond breakage accessible from T1K in azides 1 at ambient temperature. In comparison, the irradiation of azides 1 in argon matrices at 14 K lead to the formation of the corresponding triplet alkyl nitrenes (1-n), via intramolecular energy transfer from T2K. The characterization of 1-n was supported by isotope labeling, IR spectroscopy, and molecular modeling.     

Peptidotriazoles on solid phase: [1,2,3]-triazoles by regiospecific copper(i)-catalyzed 1,3-dipolar cycloadditions of terminal alkynes to azides

The cycloaddition of azides to alkynes is one of the most important synthetic routes to 1H-[1,2,3]-triazoles. Here a novel regiospecific copper(I)-catalyzed 1,3-dipolar cycloaddition of terminal alkynes to azides on solid-phase is reported. Primary, secondary, and tertiary alkyl azides, aryl azides, and an azido sugar were used successfully in the copper(I)-catalyzed cycloaddition producing diversely 1,4-substituted [1,2,3]-triazoles in peptide backbones or side chains. The reaction conditions were fully compatible with solid-phase peptide synthesis on polar supports. The copper(I) catalysis is mild and efficient (>95% conversion and purity in most cases) and furthermore, the X-ray structure of 2-azido-2-methylpropanoic acid has been solved, to yield structural information on the 1,3-dipoles entering the reaction. Novel Fmoc-protected amino azides derived from Fmoc-amino alcohols were prepared by the Mitsunobu reaction.     

Intramolecular iron(II)-catalyzed nitrogen transfer reactions of unsaturated alkoxycarbonyl azides: a facile and stereoselective route to 4,5-disubstituted oxazolidinones

Intramolecular FeII-catalyzed reactions of various unsaturated alkoxycarbonyl azides are described. The reactions occur in the presence of stoichiometric amounts of trimethyl silyl chloride employing ethanol as the solvent. The corresponding 2-alkenyloxycarbonyl azides 5, 9, 18, 20, 22, and 24 gave the products 7/8, 10/11, 19, 21, 23, and 25 of an olefin chloroamination in moderate to good yields (47-72%). The facial diastereoselectivity of the ring closing C-N-bond forming step is good both in cyclic (20, 24) and in acyclic substrates (5, 18, 22) (>90% ds). The subsequent chlorine atom transfer occurs selectively in cyclic systems (20, 24) and in systems (9b, 18) which exhibit a conformational bias in the postulated radical intermediate 14. The lifetime tau of this elusive intermediate was estimated from the loss of stereochemical information in conformationally unrestricted systems (9a, 22) and from the data obtained with a radical clock (31-->32). 2-Alkynyloxycarbonyl azides 34 and 36 also yield chloroamination products which are obtained exclusively as the (Z)-isomers 35 and 37 (81-99% yield). The products of the tert-butyl-substituted substrates 38 undergo an immediate rearrangement/solvolysis reaction in the reaction mixture and gave the 5-alkoxyoxazolidinones 39 (93-99% yield).     

Diazo compounds of the heterocyclic series

2-(N-Nitrosamino)benzimidazoles in aqueous solutions or in organic solvents are spontaneously converted to 1,3-di(2-benzimidazolyl)triazenes. Other methods for the synthesis of triazenes of the benzimidazole series and their properties are examined.     

Selective transition state stabilization via hyperconjugative and conjugative assistance: stereoelectronic concept for copper-free click chemistry

Dissection of stereoelectronic effects in the transition states (TSs) for noncatalyzed azide-alkyne cycloadditions suggests two approaches to selective transition state stabilization in this reaction. First, the formation of both 1,4- and 1,5-isomers is facilitated via hyperconjugative assistance to alkyne bending and C···N bond formation provided by antiperiplanar σ-acceptors at the propargylic carbons. In addition, the 1,5-TS can be stabilized via attractive C-H···F interactions. Although the two effects cannot stabilize the same transition state for the cycloaddition to α,α-difluorocyclooctyne (DIFO), they can act in a complementary, rather than competing, fashion in acyclic alkynes where B3LYP calculations predict up to ～1 million-fold rate increase relative to 2-butyne. This analysis of stereoelectronic effects is complemented by the distortion analysis, which provides another clear evidence of selective TS stabilization. Changes in electrostatic potential along the reaction path revealed that azide polarization may create unfavorable electrostatic interactions (i.e., for the 1,5-regioisomer formation from 1-fluoro-2-butyne and methyl azide). This observation suggests that more reactive azides can be designed via manipulation of charge distribution in the azide moiety. Combination of these effects with the other activation strategies should lead to the rational design of robust acyclic and cyclic alkyne reagents for fast and tunable "click chemistry". Further computational and experimental studies confirmed the generality of the above accelerating effects and compared them with the conjugative TS stabilization by π-acceptors.     

Spectroscopic identification of binding modes of anthracene probes and DNA sequence recognition

The binding properties of two anthracene derivatives with calf thymus DNA (CT DNA), poly(dA-dT), and poly(dG) x poly(dC) are reported. One contained bulky, cyclic cationic substituents at the 9 and 10 positions, and the other carried acylic, branched, cationic substituents. Binding of the probes to the DNA was examined by calorimetry, spectroscopy and helix melting studies. The cyclic derivative indicated exothermic binding, strong hypochromism, bathochromism, positive induced circular dichroism (CD, 300-400 nm), significant unwinding of the helix, large increases in the helix melting temperature, strong but negative linear dichroism (LD, 300-400 nm) and considerable stabilization of the helix. In contrast, the acyclic analog indicated thermoneutral binding, smaller hypochromism, no bathochromism, very weak induced CD, and no change in the helix melting temperature with any of the DNA polymers. A sharp distinction between the binding properties of the two probes is indicated, and both have intrinsic binding constants of approximately 10(6) M(-1) for the three polymers. However, when the ionic strength of the medium was lowered (10 mM NaCl), the absorption as well as CD spectral changes associated with the binding of the acyclic derivative corresponded with those of the cyclic derivative. The acyclic derivative showed large preference (10-fold) for poly(dG) x poly(dC) over poly(dA-dT), whereas the cyclic analog showed no preference. The characteristic spectroscopic signatures of the two distinct binding modes of these probes will be helpful in deciphering the interaction of other anthracene derivatives with DNA.     

New chiral ferrocenyl P,S-ligands for highly diastereo-/enantioselective catalytic [3 + 2] cycloaddition of azomethine ylides with cyclic and acyclic enones

A new family of chiral ferrocenyl P,S-ligands has been developed and successfully applied in a highly endo-selective catalytic asymmetric cycloaddition of azomethine ylides with various enones, including cyclic and acyclic α-enones. For cyclic α-enones, a [Cu(CH(3)CN)(4)]ClO(4)/(R(c),S(Fc))-2f complex catalyzed the cycloaddition to give the sole endo-cycloadducts in perfect enantioselectivities (normally 99% ee), while an AgOAc/(R(c),S(Fc))-2f catalytic system exhibited good endo/exo selectivities (endo/exo = 91/9 to 96/4) and high enantiocontrol (up to 98% ee) for acyclic α-enones.     

Enantiopurity analysis of new types of acyclic nucleoside phosphonates by capillary electrophoresis with cyclodextrins as chiral selectors

CE methods have been developed for the chiral analysis of new types of six acyclic nucleoside phosphonates, nucleotide analogs bearing [(3‐hydroxypropan‐2‐yl)‐1H‐1,2,3‐triazol‐4‐yl]phosphonic acid, 2‐[(diisopropoxyphosphonyl)methoxy]propanoic acid, or 2?(phosphonomethoxy)propanoic acid moieties attached to adenine, guanine, 2,6‐diaminopurine, uracil, and 5‐bromouracil nucleobases, using neutral and cationic cyclodextrins as chiral selectors. With the exception of the 5‐bromouracil‐derived acyclic nucleoside phosphonate with a 2‐(phosphonomethoxy)propanoic acid side chain, the R and S enantiomers of the other five acyclic nucleoside phosphonates were successfully separated with sufficient resolutions, 1.51–2.94, within a reasonable time, 13–28 min, by CE in alkaline BGEs (50 mM sodium tetraborate adjusted with NaOH to pH 9.60, 9.85, and 10.30, respectively) containing 20 mg/mL β‐cyclodextrin as the chiral selector. A baseline separation of the R and S enantiomers of the 5‐bromouracil‐derived acyclic nucleoside phosphonate with 2‐(phosphonomethoxy)propanoic acid side chain was achieved within a short time of 7 min by CE in an acidic BGE (20:40 mM Tris/phosphate, pH 2.20) using 60 mg/mL quaternary ammonium β‐cyclodextrin chiral selector. The developed methods were applied for the assessment of the enantiomeric purity of the above acyclic nucleoside phosphonates. The preparations of all these compounds were found to be synthesized in pure enantiomeric forms. Using UV absorption detection at 206 nm, their concentration detection limits were in the low micromolar range.