Infrared spectroscopy of jetcooled tautomeric dimer of 7azaindole. Excited state tautomerization of 7azaindole in a 1. Scheme 7 shows the synthesis of 4 azaindole derivatives 2b7b, 5 azaindole derivatives 2c7c, and 7 azaindole derivatives 2d7d. Acids and bases both bring about the establishment of an equilibrium between ketones or aldehydes and their enol forms, which contain a hydroxyl group directly attached to a doubly bonded carbon atom. The ir spectrum of 7 azaindole monomer, 7 azaindole reactive and nonreactive dimers, and 7 azaindole h2on n 1. Pdf synthesis and reactivity of 7azaindoles 1hpyrrolo2,3b.
All five carbon positions of the azaindole ring system can be functionalized in a predictable manner starting from the appropriately substituted azaindole 1 by directed metalation and halogenmagnesium and sulfoxidemagnesium exchange. The chemistry of azaindoles pyrrolo2,3pyridines synthesis. A reaction which involves simple proton transfer in an intramolecular fashion is called a tautomerism. Crystal structures of 7azaindole, an unusual hydrogenbonded. Azaindole survival guide syntheses of azaindoles by using classic indole. Solvent effects in the excitedstate tautomerization of 7 azaindole. Jan 19, 2011 a systematic study of the excitedstate tautomerization of 7 azaindole h2on n 1 and 2 complexes in both gas and solution phases were investigated theoretically. It is demonstrated that a biprotonic phototautomerism occurs in the dimer and in suitable ethanol solvates in fluid solvents but that the phenomenon is not observed in a rigid solvent matrix. A theoretical analysis of the double proton transfer pt in a hydrogenbonded nheterocyclic base pair is presented.
Unlike other classes of isomers, tautomeric compounds exist in mobile. The photophysical properties of 7 azatrp are very similar to those of 7 azaindole, exhibiting essentially no n 7 h tautomer form emission 16,26,27,28 and thus cannot be. The calculated timedependent density functional theory double pt barrier calculated for the concerted process of the 7azaindole c 2h dimer in the. Experimental studies of the excitedstate tautomerization of 7azaindole 7ai suggested that the intrinsic reactions occur via the concerted triple and double proton transfer mechanisms in the. A distortion of the aromatic character of 7azaindole in. The key step involved the diastereoselective alkylation of tertbutyl 1r,4rbornylideneaminoacetate 3 with 1tertbutyloxycarbonyl3iodomethyl 7 azaindole 19 derived from 3formyl 7 azaindole 14. The second equivalent may be required for a tautomerization following the cyclization of 4.
A theoretical and optical spectroscopic study of the mechanism of a. The 5bromo 7azaindole synthesis process has the advantages of being lower in cost, simple, simple and easy to operate and the like, is suitable for largescale industrial production, the purity of the product produced by means of the method is above 99%, the yield is above 74%, and the comprehensive utilization rate is high. The complex kinetics observed in the ultrafast laser dynamics studies could be attributed to any of the six or so dimeric species 5 emerging in the ultrasonic molecular beam used in the preliminary kinetic studies 11. It is wellknown that it exhibits the excitedstate double proton transfer dpt reaction.
Ketoenol tautomerism is a very common process, and is acid or base catalysed. Tautomerism is for example relevant to the behavior of amino acids and nucleic acids, two of the fundamental building blocks of life. Nevertheless, the bicyclic 6 azaindole system is widely distributed as part of the fused polycyclic structures of various groups. For a better understanding of the versatile behaviour of adenine as a ligand, a series of 10 ternary copperii complexes with deazaadenine ligands 7 azaindole 1,6, 7 trideazaadenine, h7azain, 4azabenzimidazole 1,6dideazaadenine, h4abim, 5azabenzimidazole 3,6dideazaadenine, h5abim, and 7 deaza chemistry and applications of metal complexes. Petrich examined the tautomerisation of 7azaindole 1 in. Structure of hydrogenbonded clusters of 7azaindole studied by. Exploring 6azaindole and 7azaindole rings for developing.
No dimerizaton of 7azaindole and tautomerization to 7hpyrrolo2,3bpyridine was observed in the argon matrix or glycerolwater glass. Ketoenol tautomerism in acetoacetic ester is proved by the fact that under ordinary conditions the compound gives the properties of the ketonic group as well as that of the enolic group. Using 2d ir spectroscopy, lactam and lactim tautomers of. Excited state tautomerization of 7azaindole catalyzed by pyrazole. The journal of physical chemistry b 2015, 119 6, 23022309. Our team of scientists has experience in all areas of research including life science, material science, chemical synthesis, chromatography, analytical and many others. Pdf the results of research into the chemistry of 7azaindole during the last twenty years are. For example, photoinitiated espt in 7azaindolealcohol complexes occurs within.
The calculated timedependent density functional theory double pt barrier calculated for the concerted process of the 7 azaindole c2h. Synthetic approaches for the synthesis of 7azaindole. Ketoenol tautomerism is the most common form of tautomerism and occurs in aldehydes, ketones and related compounds essentially carbonyl compounds with one or more hydrogens on the. Excitedstate double proton transfer in 3formyl 7 azaindole.
Hbonded nheterocyclic basepair phototautomerizational. The effect of n7 protonation on the irspectroscopic characteristics in solidstate and aromatic character of 7 azaindole 7ai are elucidated by means of linearpolarized irspectroscopy of oriented colloids in nematic host. The luminescence properties of nmethyl 7 azaindole and other related derivatives were compared with that of 7 azaindole. Methods and theories liudmil antonov covering the gap between basic textbooks and overspecialized scientific publications, this is the first reference available to describe this interdisciplinary topic for phd students and scientists starting in the field. Solvent effects in the excitedstate tautomerization of 7. Jan, 2004 a theoretical analysis of the double proton transfer pt in a hydrogenbonded nheterocyclic base pair is presented. Pyrazole, a five member cyclic azole, is reported here as an efficient catalyst for excited state tautomeric conversion of 7azaindole.
The molecules were evaluated by 3 hcp55,940 binding and 35 sgtp. It is demonstrated that a biprotonic phototautomerism occurs in the. In this type, one form tautomer exists as a ketone while the other exists as an enol. Substituted indoles and purines have frequently been referred to as privileged structures since they are capable of binding to multiple receptors with high affinity, and thus have applications acro. A theoretical and optical spectroscopic study of the. Facile dimerization of the picoline via a 1,4addition of the incipient benzyllithium. Structure and tautomerism of 7azaindole in the ground and excited states. Mechanism of annihilationdelayed fluorescence of 7azaindole in. For example, photo initiated espt in 7azaindolealcohol complexes occurs within. The methods used to synthesize 1b5b, 1c5c, and 1d5d are the same methods described for the synthesis of 1a5a as described in scheme 1. Electronic structures and energies for the reactant, transition state ts, and product were computed using the timedependent density functional theory tddft and complete active space selfconsistent field casscf levels with. Structure and tautomerism of 7azaindole in the ground and. Probing water microsolvation in proteins by water catalysed. Synthesis and reactivity of 7 azaindoles 1hpyrrolo2,3bpyridine article pdf available in current organic chemistry 55.
Excitedstate tautomerization of 7azaindole in water. Observation of molecularbased tuning protontransfer tautomerism pitai chou, chingyen wei, goray wu, and wensin chen department of chemistry the national chungcheng university chiayi, taiwan, r. Request pdf on mar 1, 20, shreetama karmakar and others published excited state tautomerization of 7azaindole catalyzed by pyrazole find, read and cite all the research you need on. Experimental studies of the excitedstate tautomerization of 7 azaindole 7ai suggested that the intrinsic reactions occur via the concerted triple and double proton transfer mechanisms in the. The calculated timedependent density functional theory double pt barrier calculated for the concerted process of the 7 azaindole c 2h dimer in the first excited singlet electronic state s 1 conforms well to the kinetic data and the photophysical evidence reported in this. Tautomerism, the existence of two or more chemical compounds that are capable of facile interconversion, in many cases merely exchanging a hydrogen atom between two other atoms, to either of which it forms a covalent bond. Electronic, vibrational, and electronic vibrational spectra of the 7 azaindole dimer, the 7 azaindole complex with a water molecule, and their tautomers are calculated. Oct 17, 2015 the most common type of tautomerism is that involving carbonyl, or keto, compounds and unsaturated hydroxyl compounds, or enols. The high phosphatetransfer potential of phosphoenolpyruvate results from the fact that the phosphorylated compound is trapped in the less thermodynamically favorable enol form, whereas after dephosphorylation it can assume the keto form. Excitedstate double proton transfer in 7 azaindole analogues. The calculated timedependent density functional theory double pt barrier calculated for the concerted process of the 7 azaindole c2h dimer in the first excited singlet electronic state s1 conforms well to the kinetic data and the photophysical evidence reported in this. Role of topological charge stabilization in protomeric tautomerism.
S binding assays for their allosteric modulation of the cb 1 receptor. Gene or point mutations are stable changes in genes i. Ketoenol tautomerization typically strongly favors the keto tautomer, but an important exception is the case of 1,3diketones such as acetylacetone. Electronic structures and energies for the reactant, transition state ts, and product were computed using the timedependent density functional theory tddft and complete active space selfconsistent field casscf levels. Pdf synthesis and reactivity of 7azaindoles 1hpyrrolo. Azaindoles are important targets in the pharmaceutical industry. Kasha, november 7, 2003 a theoretical analysis of the double proton transfer pt in a hydrogenbonded nheterocyclic base pair is presented. These metrics are regularly updated to reflect usage leading up to the last few days. On the 7azaindole in acetonitrile anhydrous solutions as an. The two simplest examples are of acetone and phenol. May 26, 2017 electronic, vibrational, and electronic vibrational spectra of the 7 azaindole dimer, the 7 azaindole complex with a water molecule, and their tautomers are calculated. In the excited state of the hbonded dimer, a proton goes over from the pyrrole nitrogen to the pyridine nitrogen and the fluorescence changes from violet to green.
Excited state tautomerization of 7 azaindole catalyzed by pyrazole. Chemical properties of azaindoles nu cl eoph ids am ntf g y r be carried our under vigorous conditions or long reaction times. Reaction path of the excitedstate double proton transfer esdpt in the homodimer of 7 azaindole 7ai 2 homodimer and heterodimer of 6hindolo2,3bquinoline and 7 azaindole 6hiq7ai heterodimer is computationally studied by means of intrinsic reaction coordinate irc calculations. Article views are the countercompliant sum of full text article downloads since november 2008 both pdf and html across all institutions and individuals.
Apr 30, 2010 the effect of n7 protonation on the irspectroscopic characteristics in solidstate and aromatic character of 7 azaindole 7ai are elucidated by means of linearpolarized irspectroscopy of oriented colloids in nematic host. The optical absorption and luminescence spectra of 7 azaindole and its doubly hydrogenbonded dimer were investigated as a model for the study of electronic interactions in dna base pairs. Resolution of concerted versus sequential mechanisms in. The irc path determined at the tddft level predicts the concertedasynchronous mechanism for the esdpt in. The huge potential of 7 azaindole as a hingebinding motif has encouraged many researchers to employ it as a kinase privileged fragment. The photophysical properties of 7 azatrp are very similar to those of 7 azaindole, exhibiting essentially no n 7 h tautomer form emission 16,26,27,28 and thus cannot be used for probing any. Although each gene is a potential site for a mutation, yet some genes mutate more frequently than other genes. Identification and optimisation of 7azaindole pak1. Ketoenol tautomerism definition of ketoenol tautomerism. Electrophilic substitution in the 3position of 1benzyl4methyl5cyano6chloro 7 azaindole requires more severe conditions than in 7 azaindoles without the 5cyanosubstituent. A comparison between the data of neutral and protonated form of 7ai is done. Tautomerism is the phenomenon of chemical isomers structures that have the same atomic composition, e.
Sar exploration in the selectivity pocket and solvent tail regions was conducted to understand and optimise pak1 potency and selectivity against targeted kinases. Equilibrium thermodynamics of a ketoenol tautomerism reaction 63 fall 2004. Excited singlet states of dimertautomers were populated by mixed annihilation of monomer and dimertautomer triplet states. Concertedasynchronous reaction path of the excitedstate.
The application of the sonogashira coupling in combination with the trifluoroacetic acidacetic anhydride mixture in acetonitrile at 100 c, yielded substituted7azaindole derivatives 167 in good yields for chapter 5 of this thesis. Some of the important types of gene mutations of dna chain are. Transition states are considered based on the analysis of frequencies and shapes of lowfrequency vibrations and the mulliken charge redistribution. There are several types of tautomerism of which ketoenol tautomerism is the most important. We synthesized 6 and 7 azaindole 2carboxamides and their indole2carboxamide counterparts. A liganded pak1 crystal structure was utilised to guide compound d. These studies confirm our interpretation of excitedstate twoproton tautomerism in 7 azaindole hydrogenbonded dimer. Ketoenol tautomerization by jay our mission is to provide a free, worldclass education to anyone, anywhere. Watercatalyzed excitedstate protontransfer reactions in 7 azaindole and its analogues. Department of chemistry, graduate school of science, kobe university, nadaku, kobe 6578501, japan7 azaindole 7 ai dimer is a very attractive species as a model system of neucleicacid base pair. For 7azaindole, electrophilic substitution can be summarized as follows. The performed quantum chemical calculation of chemical reactions enabled the. The dimer of the 7 azaindole is a double hydrogenbonded dimer, called the 7 azaindole pairing, pairing that is also found in adenine crystals but not naturally in dna. Double proton transfer reaction of 7azaindole dimer and.
Effect of deuteration of the pyrrolic hydrogen on luminescence is investigated. Note that in all the examples of ketoenol tautomerism the two isomeric forms are interconvertible by v tautomerism. The products are fully substituted azaindoles of type 2. Infrared spectra of nh and nd stretch bands of the 7 azaindole 7 ai dimer and its tautomeric dimer are observed to investigate a deuteration effect on the spectra and also a groundstate double. Structure and tautomerism of 7 azaindole in the ground and excited states. The photophysical properties of 7azatrp are very similar to those of 7azaindole, exhibiting essentially no n7h tautomer form emission16. A novel series of pak1 inhibitors was discovered from a kinase directed screen. A model base pair for such a biprotonic phototautomeric shift is 7azaindole. Here we present data on structural characterization, suitable urinary consumption markers and preliminary pharmacokinetic data. Tautomerism tautomers are isomers of a compound which differ only in the position of the protons and electrons. A central issue in doubleproton transfer pt reactions is whether a sequential stepwise or a concerted mechanism is applicable at.
Excited state tautomerization of 7 azaindole in a 1. Direct observation of groundstate lactamlactim tautomerization. Ketoenol tautomerism definition is tautomerism in which the keto and enol forms of a compound as ethyl acetoacetate are in equilibrium. Dec 19, 2008 the lithium diisopropylamide ldamediated condensation of 2fluoro3picoline and benzonitrile to form 2phenyl 7 azaindole via a chichibabin cyclization is described. View enhanced pdf access article on wiley online library html view download pdf for offline viewing. Introduction, history, and recent developments in experimental and theoretical methods peter j. The lithium diisopropylamide ldamediated condensation of 2fluoro3picoline and benzonitrile to form 2phenyl 7 azaindole via a chichibabin cyclization is described. Excitedstate tautomerization in the 7azaindoleh2on n. Consequently, the assertion of kwon and zewail 7,8 that the rate of proton transfer in 7 azaindole dimers is significantly dependent on the solvent polarity and its stepwise mechanism for the process is not rightly stated as no c2h dimer is formed in the medium used to record their femtosecond time resolved and fluorescence spectroscopic.
Other examples of this type of tautomerism can be found in bullvalene, and in open and closed forms of certain heterocycles, such as organic azides and tetrazoles, or mesoionic munchnone and acylamino ketene. Hbonded nheterocyclic basepair phototautomerizational potential. Us20040063746a1 indole, azaindole and related heterocyclic. The experimental data are supported by theoretical ab initio ones and experimental uv. Electronic spectra and tautomerism of hydrogenbonded. Synthesis of a 7azaindole by chichibabin cyclization. However, the most widely studied example of ketoenol tautomerism is that of acetoacetic ester ethyl acetoacetate. Inhibition of lightinduced tautomerization of 7azaindole. Ketoenol tautomerism is important in several areas of biochemistry. A systematic study of the excitedstate tautomerization of 7 azaindole h2on n 1 and 2 complexes in both gas and solution phases were investigated theoretically. In addition, the azaindole backbone was subjected to typical coupling reactions.
R 7 azatryptophan 2 from commercially available 7 azaindole 4 is described. They included consideration of the possibility of mutations by tautomeric proton. Valence tautomerism requires a change in molecular geometry and should not be confused with canonical resonance structures or mesomers. Reaction of 4chloro7azaindole with a secondary amine results in normal substitution of the halogen but. Ketoenol tautomerization by sal video khan academy. Fub7aica was purchased online and analytically identified as 5f. Excited state tautomerization of 7azaindole catalyzed by. The photophysical properties of 7azatrp are very similar to those of 7 azaindole, exhibiting essentially no n7h tautomer form emission16. Double proton transfer reaction of 7azaindole dimer and complexes studied by timeresolved thermal lensing technique. The 7 azaindole molecule has been the subject of numerous studies because its dimer has been recognized as a simplified model for the hydrogenbonded base pair of dna and could provide information on the possible role of tautomerism in mutation. The normal violet structured fluorescence of 7 azaindole monomer becomes a broad green fluorescence in the tautomer. The 7azaindole molecule has been the subject of numerous studies because its dimer has been recognized as a simplified model for the hydrogenbonded base pair of dna and could provide information on the possible role of tautomerism in mutation. The 7 azaindole 2carboxamides lost the ability to bind to the cb 1 receptor. The doubly hbonded dimer of 7 azaindole 7 ai has been studied exhaustively as a model prototype for dna basepair tautomerization, as it is recognized to undergo a biprotonic transfer 1 on photoexcitation.