Co-reporter:Christopher J. Evoniuk, Gabriel dos Passos Gomes, Sean P. Hill, Satoshi Fujita, Kenneth Hanson, and Igor V. Alabugin
Journal of the American Chemical Society November 15, 2017 Volume 139(Issue 45) pp:16210-16210
Publication Date(Web):October 16, 2017
DOI:10.1021/jacs.7b07519
An intramolecular oxidative C(sp3)–H amination from unprotected anilines and C(sp3)–H bonds readily occurs under mild conditions using t-BuOK, molecular oxygen and N,N-dimethylformamide (DMF). Success of this process, which requires mildly acidic N–H bonds and an activated C(sp3)–H bond (BDE < 85 kcal/mol), stems from synergy between basic, radical, and oxidizing species working together to promote a coordinated sequence of deprotonation: H atom transfer and oxidation that forges a new C–N bond. This process is applicable for the synthesis of a wide variety of N-heterocycles, ranging from small molecules to extended aromatics without the need for transition metals or strong oxidants. Computational results reveal the mechanistic details and energy landscape for the sequence of individual steps that comprise this reaction cascade. The importance of base in this process stems from the much greater acidity of transition state and product for the 2c,3e C–N bond formation relative to the reactant. In this scenario, selective deprotonation provides the driving force for the process.
Co-reporter:Gabriel dos Passos Gomes and Igor V. Alabugin
Journal of the American Chemical Society March 8, 2017 Volume 139(Issue 9) pp:3406-3406
Publication Date(Web):February 10, 2017
DOI:10.1021/jacs.6b11054
The synergy between bond formation and bond breaking that is typical for pericyclic reactions is lost in their mechanistic cousins, cycloaromatization reactions. In these reactions, exemplified by the Bergman cyclization (BC), two bonds are sacrificed to form a single bond, and the reaction progress is interrupted at the stage of a cyclic diradical intermediate. The catalytic power of Au(I) in BC stems from a combination of two sources: stereoelectronic assistance of C–C bond formation (i.e., “LUMO umpolung”) and crossover from a diradical to a zwitterionic mechanism that takes advantage of the catalyst’s dual ability to stabilize both negative and positive charges. Not only does the synergy between the bond-forming and charge-delocalizing interactions lead to a dramatic (>hundred-billion-fold) acceleration, but the evolution of the two effects results in continuous reinforcement of the substrate/catalyst interaction along the cyclization path. This cooperativity converts the BC into the first example of an aborted [3,3] sigmatropic shift where the pericyclic “transition state” becomes the most stable species on the reaction hypersurface. Aborting the pericyclic path facilitates trapping of cyclic intermediate by a variety of further reactions and provides a foundation for the discovery of new modes of reactivity of polyunsaturated substrates. The application of distortion/interaction analysis allows us to quantify the increased affinity of Au-catalysts to the Bergman cyclization transition state as one of the key components of the large catalytic effect.
Co-reporter:Eusebio Juaristi, Gabriel dos Passos Gomes, Alexander O. Terent’ev, Rafael Notario, and Igor V. Alabugin
Journal of the American Chemical Society August 9, 2017 Volume 139(Issue 31) pp:10799-10799
Publication Date(Web):July 12, 2017
DOI:10.1021/jacs.7b05367
The first systematic study of the intramolecular α-effect, both in the stable ground-state structures and in the high-energy intermediates, was accomplished using the anomeric effect as an internal stereoelectronic probe. Contrary to the expectations based on the simple orbital mixing model, the lone pairs in a pair of neutral directly connected heteroatoms are not raised in energy to become stronger donors toward adjacent σ- and π-acceptors. Instead, the key n(X-Y)→σ*C-F interactions (X,Y = O,N) in the “α-systems” (both acyclic and constrained within a heterocyclohexane frame) are weaker than nX→σ*C-F interactions in “normal” systems. Surprisingly, polar solvent effects increase the apparent magnitude of α-effect as measured via increase in the anomeric stabilization. This behavior is opposite to the solvent dependence of normal systems where the anomeric effect is severely weakened by polar solvents. This contrasting behavior reflects the different balance of electrostatic and conjugative interactions in the two types of anomeric systems: the α-systems suffer less from the unfavorable orientation of bond dipoles in the equatorial conformer, a destabilizing electrostatic effect that is shielded by the polar environments. A weak α-effect is brought to life when the buttressing α-heteroatom bears a negative charge. However, electrostatic components mask the role of stabilizing orbital interactions. In contrast, the increased electron demand in carbocations and related electron-deficient TS- like structures does not lead to activation of the α-effect. As a consequence, we observed that ethers are better radical- and cation-stabilizing groups than peroxides. The latter finding should have significant implications for understanding the mechanistic complexity associated with the interaction of carbonyl compounds with hydroperoxides and H2O2 in acidic media, as such reactions involve α-cationic intermediates.
Co-reporter:Christopher J. Evoniuk, Gabriel dos Passos Gomes, Michelle Ly, Frankie D. White, and Igor V. Alabugin
The Journal of Organic Chemistry April 21, 2017 Volume 82(Issue 8) pp:4265-4265
Publication Date(Web):March 30, 2017
DOI:10.1021/acs.joc.7b00262
Selective addition of radicals to isonitriles can be harnessed for initiating reaction cascades designed to overcome the stereoelectronic restrictions on homoallylic ring expansion in alkyne reactions and to develop a new general route for the preparation of N-heteroaromatics. This method utilizes alkenes as synthetic equivalents of alkynes by coupling homoallylic ring expansion to yield the formal “6-endo” products with aromatization via stereoelectronically assisted C–C bond scission. Computational analysis of the homoallyic expansion potential energy surface reveals that the indirect 5-exo/3-exo/retro-3-exo path is faster than the direct 6-endo-trig closure, revealing the general exo-preference for the cyclization processes.
Co-reporter:Gabriel dos Passos Gomes;Christopher J. Evoniuk;Michelle Ly
Organic & Biomolecular Chemistry 2017 vol. 15(Issue 19) pp:4135-4143
Publication Date(Web):2017/05/16
DOI:10.1039/C7OB00527J
Chemoselective addition of radicals to isonitriles can be harnessed for initiating reaction cascades designed to overcome the stereoelectronic restrictions on homoallylic ring expansion in alkyne reactions and to develop a new general route for the preparation of N-heteroaromatics. This method utilizes alkenes as synthetic equivalents of alkynes by coupling homoallylic ring expansion to yield the formal “6-endo” products with aromatization via stereoelectronically assisted C–C bond scission. Detailed computational analysis of the individual steps of the homoallylic expansion sequence maps effects of substituents and structural constraints on this multi-step potential energy surface.
Co-reporter:Gabriel dos Passos Gomes;Dr. Ivan A. Yaremenko;Peter S. Radulov;Dr. Roman A. Novikov; Vladimir V. Chernyshev; Alexer A. Korlyukov; Gennady I. Nikishin; Igor V. Alabugin; Alexer O. Terent'ev
Angewandte Chemie 2017 Volume 129(Issue 18) pp:5037-5041
Publication Date(Web):2017/04/24
DOI:10.1002/ange.201610699
AbstractThe value of stereoelectronic guidelines is illustrated by the discovery of a convenient, ozone-free synthesis of bridged secondary ozonides from 1,5-dicarbonyl compounds and H2O2. The tetraoxane products generally formed in reactions of carbonyl and dicarbonyl compounds with H2O2 were not detected because the structural distortions imposed on the tetraoxacyclohexane subunit in [3.2.2]tetraoxanonanes by the three-carbon bridge leads to the partial deactivation of anomeric effects. The new procedure is readily scalable to produce gram quantities of the ozonides. This reaction enables the selective preparation of ozonides without the use of ozone.
Co-reporter:Igor V. Alabugin, Trevor Harris
Chem 2017 Volume 2, Issue 6(Volume 2, Issue 6) pp:
Publication Date(Web):8 June 2017
DOI:10.1016/j.chempr.2017.05.018
In this issue of Chem, Qin and coworkers report a tour-de-force effort that leverages a photoredox approach for the generation of N-centered radicals from N–H bonds into the total synthesis of 33 natural products across four different indole alkaloid families.
Co-reporter:Trevor Harris, Gabriel dos Passos Gomes, Suliman Ayad, Ronald J. Clark, ... Igor V. Alabugin
Chem 2017 Volume 3, Issue 4(Volume 3, Issue 4) pp:
Publication Date(Web):12 October 2017
DOI:10.1016/j.chempr.2017.07.011
•Increased “click” reactivity through remote activation•Gram-scale, one-step preparation of enantiopure cycloalkynes•Twisted cyclodecynes approach reactivity of cyclooctynes•Experiments and computational analysis reveal activating role of remote interactionsNon-catalyzed alkyne/azide cycloaddition, a widely used “click” reaction in interdisciplinary scientific research, offers a modular, practical, and metal-free approach to building molecular complexity in environments where toxic and redox active species should be avoided. In this paper, we describe a fundamental concept for increasing “click” reactivity through remote interactions with the hope of leading to the development of creative technological innovations. This work also introduces axial chirality as a molecular property that can be achieved by “click” chemistry, which opens the door for the future controlled creation of chiral objects and environments from achiral small molecules, polymers, and surfaces.The “twisted and bent” cyclodecyne structural motif, intertwined with dormant electronic effects, opens a conceptually powerful way to control “click” reactivity. The endocyclic heteroatoms of cyclodecynes provide dual electronic activation via hyperconjugative (direct) and conjugative (remote) effects. These effects are weakened by the geometric constraints imposed by the twisted backbone, but structural reorganization in the transition state (TS) removes these constraints and unlocks the power of remote electronic effects for selective TS stabilization. Gram-scale synthesis and purification by recrystallization make this an efficient and practical approach to enantiopure cycloalkynes. Experimental kinetics confirm that these twisted cyclodecynes can be more reactive toward azides than activated cyclononynes and approach the reactivity of cyclooctynes. Furthermore, cycloalkynes with a twisted polyaromatic backbone can potentially add axial chirality to the “click” chemistry toolbox.Download high-res image (123KB)Download full-size image
Co-reporter:Paul W. Peterson, Nikolay Shevchenko, Boris Breiner, Mariappan Manoharan, Forat Lufti, Jess Delaune, Margaret Kingsley, Kirill Kovnir, and Igor V. Alabugin
Journal of the American Chemical Society 2016 Volume 138(Issue 48) pp:15617-15628
Publication Date(Web):November 6, 2016
DOI:10.1021/jacs.6b08540
Generally, the long-range electronic communication between spatially orthogonal orbitals is inefficient and limited to field and inductive effects. In this work, we provide experimental evidence that such communication can be achieved via intramolecular electron transfer between two degenerate and mutually orthogonal frontier molecular orbitals (MOs) at the transition state. Interaction between orthogonal orbitals is amplified when the energy gap between these orbitals approaches zero, or at an “orbital crossing”. The crossing between two empty or two fully occupied MOs, which do not lead to stabilization, can be “activated” when one of the empty MOs is populated (i.e., electron injection) or one of the filled MOs is depopulated (i.e., hole injection). In reductive cycloaromatization reactions, such crossings define transition states with energies defined by both the in-plane and out-of-plane π-systems. Herein, we provide experimental evidence for the utility of this concept using orbital crossings in reductive C1–C5 cycloaromatization reactions of enediynes. Communication with remote substituents via orbital crossings greatly enhances regioselectivity of the ring closure step in comparison to the analogous radical cyclizations. We also present photophysical data pertaining to the efficiency of electron injection into the benzannelated enediynes.
Co-reporter:Dinesh V. Vidhani; Marie E. Krafft
Journal of the American Chemical Society 2016 Volume 138(Issue 8) pp:2769-2779
Publication Date(Web):February 5, 2016
DOI:10.1021/jacs.5b12920
Pericyclic reactions bypass high-energy reactive intermediates by synchronizing bond formation and bond cleavage. The present work offers two strategies for uncoupling these two processes and converting concerted processes into their “interrupted” versions by combining Au(I) catalysis with electronic and stereoelectronic factors. First, we show how the alignment of the C3–C4 bond with the adjacent π systems can control the reactivity and how the concerted scission of the central σ bond is prevented in the boat conformation. Second, the introduction of a fluorine atom at C3 also interrupts the sigmatropic shift and changes the rate-determining step of the interrupted cascade from the 6-endo-dig nucleophilic attack to the fragmentation of the central C3–C4 bond. Furthermore, this effect strongly depends on the relative orientation of the C–F bond toward the developing cationic center. The equatorial C–F bond has a much greater destabilizing effect on TS2 due to the more efficient through-bond interaction between the acceptor and the cationic π system. In contrast, the axial C–F bond is not aligned with the bridging C–C bonds and does not impose an equally strong deactivating stereoelectronic effect. These differences illustrate that the competition between concerted and interrupted pericyclic pathways can be finely tuned via a combination of structural and electronic effects modulated by conformational equilibria. The combination of Au(I) catalysis and C–F-mediated stereoelectronic gating delays the central bond scission, opening access to the interrupted Cope rearrangements and expanding the scope of this classic reaction to the design of new cascade transformations.
Co-reporter:Christopher J. Evoniuk, Sean P. Hill, Kenneth Hanson and Igor V. Alabugin
Chemical Communications 2016 vol. 52(Issue 44) pp:7138-7141
Publication Date(Web):04 May 2016
DOI:10.1039/C6CC03106D
A new method for intramolecular C–H oxidative amination is based on a FeCl3-mediated oxidative reaction of anilines with activated sp3 C–H bonds. The amino group plays multiple roles in the reaction cascade: (1) as the activating group in single-electron-transfer (SET) oxidation process, (2) as a directing group in benzylic/allylic C–H activation at a remote position, and (3) internal nucleophile trapping reactive intermediates formed from the C–H activation steps. These multielectron oxidation reactions proceed with catalytic amounts of Fe(III) and inexpensive reagents.
Co-reporter:Kamalkishore Pati, Gabriel dos Passos Gomes, Trevor Harris, and Igor V. Alabugin
Organic Letters 2016 Volume 18(Issue 5) pp:928-931
Publication Date(Web):February 17, 2016
DOI:10.1021/acs.orglett.5b03522
Selective gold(I)-catalyzed rearrangement of aromatic methoxypropynyl acetals leads to fused catechol ethers (1,2-dialkoxynapthalenes) in excellent yields. Furthermore, this process extends to the analogous heterocyclic and aliphatic substrates. Alkyne activation triggers nucleophilic addition of the acetal oxygen that leads to an equilibrating mixture of oxonium ions of similar stability. This mixture is “kinetically self-sorted” via a highly exothermic cyclization. Selective formation of 1,2-dialkoxy naphthalenes originates from chemoselective aromatization of the cyclic intermediate via 1,4-elimination of methanol.
Co-reporter:Kemal Kaya, Saumya Roy, Juan Carlos Nogues, Juan Camilo Rojas, Zlatko Sokolikj, Diego A. R. Zorio, and Igor V. Alabugin
Journal of Medicinal Chemistry 2016 Volume 59(Issue 18) pp:8634-8647
Publication Date(Web):August 15, 2016
DOI:10.1021/acs.jmedchem.6b01164
We report pH-switching properties of the new family of dipeptide–acetylene conjugates where pH-gated light-activated double-strand (ds) DNA cleavage is controlled by variations in electronic and geometric parameters. The conjugates have higher activities at the slightly acidic pH values that separate normal and cancerous tissue (pH < 7). This favorable pH dependence originates from several elements of structural design. Basicities of the two amines determine the threshold pH range where the changes in binding and reactivity are observed, whereas the distance between the two amino groups and the hydrophobic aryl alkyne moiety can further modulate DNA binding. The changes of the protonation state from a neutral molecule to a dication results in dramatically increased efficiency of ds DNA photocleavage, the most therapeutically valuable type of DNA cleavage.
Co-reporter:Stefan Bresch;Robert Wandell;Huihui Wang
Plasma Chemistry and Plasma Processing 2016 Volume 36( Issue 2) pp:553-584
Publication Date(Web):2016 March
DOI:10.1007/s11090-015-9686-x
A non-thermal continuous flow plasma reactor with a liquid water stream and argon carrier gas is shown to convert n-hexane and water into alcohols, alkenes, ketones, hydroperoxides, alpha-hydroxy-ketones and diketones. Fragmented (short chain) primary alcohols, fragmented aldehydes and fragmented carboxylic acids are also formed. The variation of the supply voltage and oxygen concentration allows moderate fine-tuning of yield and selectivity of this organic “diversity-oriented” synthetic process. A (pH based) procedure for rapid separation of the organic hydroperoxides has been developed. Computationally determined thermodynamic and kinetic parameters of several reaction pathways support their feasibility. The construction of a mechanistic pathway map was accomplished, providing deeper insight into this radical and plasma based transformation process.
Co-reporter:Trevor Harris, Gabriel dos Passos Gomes, Ronald J. Clark, and Igor V. Alabugin
The Journal of Organic Chemistry 2016 Volume 81(Issue 14) pp:6007-6017
Publication Date(Web):June 15, 2016
DOI:10.1021/acs.joc.6b01052
Direct evidence for the formation of alkoxy radicals is reported in radical cascades using traceless directing groups. Despite the possibility of hydrogen abstraction in the fragmenting step, followed by loss of R-OH, β-scission is preferred for the formation of alkoxy radicals. For the first time, the C-O radical was intermolecularly trapped using a silyl enol ether. Various C–X fragmenting groups were explored as possible traceless directing groups for the preparation of extended polyaromatics. Computational evidence shows that a combination of aromatization, steric and stereoelectronic effects assists the fragmentation to alkoxy radicals. Additionally, a new through-space interaction was discovered between O and Sn in the fragmentation as a specific transition state stabilizing effect.
Co-reporter:Rana K. Mohamed; Sayantan Mondal; Brian Gold; Christopher J. Evoniuk; Tanmay Banerjee; Kenneth Hanson
Journal of the American Chemical Society 2015 Volume 137(Issue 19) pp:6335-6349
Publication Date(Web):April 23, 2015
DOI:10.1021/jacs.5b02373
Chemoselective interaction of aromatic enynes with Bu3Sn radicals can be harnessed for selective cascade transformations, yielding either Sn-substituted naphthalenes or Sn-indenes. Depending on the substitution at the alkene terminus, the initial regioselective 5-exo-trig cyclizations can be intercepted at the 5-exo stage via either hydrogen atom abstraction or C–S bond scission or allowed to proceed further to the formal 6-endo products via homoallylic ring expansion. Aromatization of the latter occurs via β-C–C bond scission, which is facilitated by 2c,3e through-bond interactions, a new stereoelectronic effect in radical chemistry. The combination of formal 6-endo-trig cyclization with stereoelectronically optimized fragmentation allows the use of alkenes as synthetic equivalents of alkynes and opens a convenient route to α-Sn-substituted naphthalenes, a unique launching platform for the preparation of extended polyaromatics.
Co-reporter:Rana K. Mohamed; Sayantan Mondal; Kjell Jorner; Thais Faria Delgado; Vladislav V. Lobodin; Henrik Ottosson
Journal of the American Chemical Society 2015 Volume 137(Issue 49) pp:15441-15450
Publication Date(Web):November 4, 2015
DOI:10.1021/jacs.5b07448
The last missing example of the four archetypical cycloaromatizations of enediynes and enynes was discovered by combining a twisted alkene excited state with a new self-terminating path for intramolecular conversion of diradicals into closed-shell products. Photoexcitation of aromatic enynes to a twisted alkene triplet state creates a unique stereoelectronic situation, which is facilitated by the relief of excited state antiaromaticity of the benzene ring. This enables the usually unfavorable 5-endo-trig cyclization and merges it with 5-exo-dig closure. The 1,4-diradical product of the C1–C5 cyclization undergoes internal H atom transfer that is coupled with the fragmentation of an exocyclic C–C bond. This sequence provides efficient access to benzofulvenes from enynes and expands the utility of self-terminating aromatizing enyne cascades to photochemical reactions. The key feature of this self-terminating reaction is that, despite the involvement of radical species in the key cyclization step, no external radical sources or quenchers are needed to provide the products. In these cascades, both radical centers are formed transiently and converted to the closed-shell products via intramolecular H-transfer and C–C bond fragmentation. Furthermore, incorporating C–C bond cleavage into the photochemical self-terminating cyclizations of enynes opens a new way for the use of alkenes as alkyne equivalents in organic synthesis.
Co-reporter:Gabriel dos Passos Gomes, Vera Vil', Alexander Terent'ev and Igor V. Alabugin
Chemical Science 2015 vol. 6(Issue 12) pp:6783-6791
Publication Date(Web):07 Sep 2015
DOI:10.1039/C5SC02402A
The unusual stability of bis- and tris-peroxides contradicts the conventional wisdom – some of them can melt without decomposition at temperatures exceeding 100 °C. In this work, we disclose a stabilizing stereoelectronic effect that two peroxide groups can exert on each other. This stabilization originates from strong anomeric nO → σ*CO interactions that are absent in mono-peroxides but reintroduced in molecules where two peroxide moieties are separated by a CH2 group. Furthermore, such effects can be induced by other σ-acceptors and amplified by structural constraints imposed by cyclic and bicyclic frameworks.
Co-reporter:Christopher J. Evoniuk, Michelle Ly and Igor V. Alabugin
Chemical Communications 2015 vol. 51(Issue 64) pp:12831-12834
Publication Date(Web):08 Jul 2015
DOI:10.1039/C5CC04391C
Stereoelectronic restrictions on homoallylic ring expansion in alkyne cascades can be overcome by using alkenes as synthetic equivalents of alkynes in reaction cascades that are terminated by C–C bond fragmentation. Implementation of this approach using Mn(III)-mediated reaction of o-alkenyl isocyanides and boronic acids leads to efficient synthesis of substituted quinolines.
Co-reporter:Igor V. Alabugin;Stefan Bresch ;Gabriel dos Passos Gomes
Journal of Physical Organic Chemistry 2015 Volume 28( Issue 2) pp:147-162
Publication Date(Web):
DOI:10.1002/poc.3382
This review outlines fundamental factors responsible for hybridization trends in organic and main group compounds. Hybridization is a classic chemical concept that transcends textbook organic chemistry. Hybridization effects are omnipresent, and their understanding is essential for the unraveling of many structural and reactivity puzzles. Even when they are masked by a stronger effect (e.g., allylic delocalization), they still lurk below the surface. Overriding such effects comes with a penalty, whereas incorporation into reaction design provides an efficient tool for the control of reactivity. Copyright © 2014 John Wiley & Sons, Ltd.
Co-reporter:Kemal Kaya;Madeleine Johnson
Photochemistry and Photobiology 2015 Volume 91( Issue 3) pp:748-758
Publication Date(Web):
DOI:10.1111/php.12412
Abstract
Photochemical activation of meta-diynes incapable of Bergman and C1–C5 cyclizations still leads to efficient double-strand DNA cleavage. Spatial proximity of the two arylethynyl groups is not required for efficient DNA photocleavage by the enediyne-lysine conjugates. Efficiency of the cleavage is a function of the external pH and DNA damage is strongly enhanced at pH < 7. The pH-dependence of the DNA photocleavage activity stems from the protonation states of lysine amino groups, the internal electron donors responsible for intramolecular PET quenching and deactivation of the photoreactive excited states. DNA-binding analysis suggests intercalative DNA binding for phenyl substituted conjugate and groove binding for TFP-substituted conjugate. Additional insights in the possible mechanism for DNA damage from the ROS (Reactive Oxygen Species) scavenger experiments found that generation of singlet oxygen is partially involved in the DNA damage.
Co-reporter:Sergei F. Vasilevsky, Maria P. Davydova, Victor I. Mamatuyk, Nadezhda V. Pleshkova, Dmitry S. Fadeev, Igor V. Alabugin
Mendeleev Communications 2015 Volume 25(Issue 5) pp:377-379
Publication Date(Web):September–October 2015
DOI:10.1016/j.mencom.2015.09.021
Reaction of 3-aryl-1-(3,4,5-trimethoxyphenyl)prop-2-yn-1-ones with (+)-pseudoephedrine leads to products of alkyne moiety cleavage, namely, 1-(3,4,5-trimethoxyphenyl)ethanone and N-(1-hydroxy-1-phenylprop-2-yl)-N-methylbenzamides. In the course of the process one of alkyne carbons undergoes a formal reduction to a Me group, whereas the other one is oxidized to a C(O)NRR’ moiety.
Co-reporter:Kamalkishore Pati, Christopher Michas, David Allenger, Ilya Piskun, Peter S. Coutros, Gabriel dos Passos Gomes, and Igor V. Alabugin
The Journal of Organic Chemistry 2015 Volume 80(Issue 23) pp:11706-11717
Publication Date(Web):August 6, 2015
DOI:10.1021/acs.joc.5b01014
The majority of Sn-mediated cyclizations are reductive and, thus, cannot give a fully conjugated product. This is a limitation in the application of Sn-mediated radical cascades for the preparation of fully conjugated molecules. In this work, we report an oxidatively terminated Bu3Sn-mediated cyclization of an alkyne where AIBN, the commonly used initiator, takes on a new function as an oxidative agent. Sn-mediated radical transformation of biphenyl aryl acetylenes into functionalized phenanthrenyl stannanes can be initiated via two potentially equilibrating vinyl radicals, one of which can be trapped by the fast 6-endoclosure at the biphenyl moiety in good to excellent yields. The efficient preparation of Sn-substituted phenanthrenes opens access to convenient building blocks for the construction of larger polyaromatics.
Co-reporter:Sergei F. Vasilevsky, Denis S. Baranov, Victor I. Mamatyuk, Dmitry S. Fadeev, Yurii V. Gatilov, Aleksandr A. Stepanov, Nadezhda V. Vasilieva, and Igor V. Alabugin
The Journal of Organic Chemistry 2015 Volume 80(Issue 3) pp:1618-1631
Publication Date(Web):January 9, 2015
DOI:10.1021/jo502543b
Reductive dimerization of acetylenic anthraquinones provides synthetic access to flexible nonplanar polyaromatics with a tetracenedione core. In solution, these nonplanar, contorted polycycles exist as equilibrating mixtures of two symmetric conformers. The fused tetracenediones are easily reduced and exhibit rich electrochemical behavior.
Co-reporter:Kamalkishore Pati; Gabriel dos Passos Gomes; Trevor Harris; Audrey Hughes; Hoa Phan; Tanmay Banerjee; Kenneth Hanson
Journal of the American Chemical Society 2014 Volume 137(Issue 3) pp:1165-1180
Publication Date(Web):December 24, 2014
DOI:10.1021/ja510563d
We report the first example of a traceless directing group in a radical cascade. The chemo- and regioselectivity of the initial attack in skipped oligoalkynes is controlled by propargyl OR moiety. Radical translocations lead to the boomerang return of the radical center to the site of initial attack where it assists the elimination of the directing functionality via β-scission in the last step of the cascade. The Bu3Sn moiety continues further via facile reactions with electrophiles as well as Stille and Suzuki cross-coupling reactions. This selective radical transformation opens a new approach for the controlled transformation of skipped oligoalkynes into polycyclic ribbons of tunable dimensions.
Co-reporter:Kamalkishore Pati
European Journal of Organic Chemistry 2014 Volume 2014( Issue 19) pp:3986-3990
Publication Date(Web):
DOI:10.1002/ejoc.201402469
Abstract
Au-catalyzed cycloisomerization of aryl propargyl ethers provides controlled transition from alkyne to carbonyl chemistry followed up by a Petasis–Ferrier rearrangement/aromatization cascade leading to substituted biaryls with functionalized naphthalene cores.
Co-reporter:Brian Gold, Paratchata Batsomboon, Gregory B. Dudley, and Igor V. Alabugin
The Journal of Organic Chemistry 2014 Volume 79(Issue 13) pp:6221-6232
Publication Date(Web):June 13, 2014
DOI:10.1021/jo500958n
Our recent work has provided an alternative strategy for acceleration of azide/alkyne cycloadditions via selective transition state (TS) stabilization. Optimization of hyperconjugative assistance, provided by the antiperiplanar arrangement of propargylic σ-acceptors relative to the forming bonds, is predicted to relieve strain in cyclooctynes while providing large acceleration to the cycloaddition. The present work investigates this strategy in alkynyl crown ethers, where propargylic C–O bonds contained within the macrocycle are constrained close to proper alignment for hyperconjugative assistance. Preorganization of σ-acceptors into the optimal arrangement for hyperconjugative interactions may alleviate a portion of the entropic penalty for reaching the TS. Optimal alignment can be reinforced, and transition-state stabilization can be further amplified by binding positively charged ions to the crown ether core, highlighting the potential for applications in ion sensing.
Co-reporter:Dr. Sayantan Mondal;Brian Gold;Rana K. Mohamed ;Dr. Igor V. Alabugin
Chemistry - A European Journal 2014 Volume 20( Issue 28) pp:8664-8669
Publication Date(Web):
DOI:10.1002/chem.201402843
Abstract
Radical cascades terminated by β-scission of exocyclic CC bonds allow for the formation of aromatic products. Whereas β-scission is common for weaker bonds, achieving this reactivity for carbon–carbon bonds requires careful design of radical leaving groups. It has now been found that the energetic penalty for breaking a strong σ-bond can be compensated by the gain of aromaticity in the product and by the stabilizing two-center, three-electron “half-bond” present in the radical fragment. Furthermore, through-bond communication of a radical and a lone pair accelerates the fragmentation by selectively stabilizing the transition state. The stereoelectronic design of radical leaving groups leads to a new, convenient route to Sn-functionalized aromatics.
Co-reporter:Dr. Kamalkishore Pati;Audrey M. Hughes;Hoa Phan ; Igor V. Alabugin
Chemistry - A European Journal 2014 Volume 20( Issue 2) pp:390-393
Publication Date(Web):
DOI:10.1002/chem.201304092
Abstract
Cascade radical transformations of acyclic precursors open efficient, convenient and atom-economical access to functionalized compounds of increased structural complexity. This report describes a selective sequence of 5-exo-dig and 6-exo-dig cyclizations followed by attack at a pendant aromatic moiety and rearomatization.
Co-reporter:Dinesh V. Vidhani, Marie E. Krafft, and Igor V. Alabugin
The Journal of Organic Chemistry 2014 Volume 79(Issue 1) pp:352-364
Publication Date(Web):December 4, 2013
DOI:10.1021/jo402505f
The combination of experiments and computations reveals unusual features of stereoselective Rh(I)-catalyzed transformation of propargyl vinyl ethers into (E,Z)-dienals. The first step, the conversion of propargyl vinyl ethers into allene aldehydes, proceeds under homogeneous conditions via a “cyclization-mediated” mechanism initiated by Rh(I) coordination at the alkyne. This path agrees well with the small experimental effects of substituents on the carbinol carbon. The key feature revealed by the computational study is the stereoelectronic effect of the ligand arrangement at the catalytic center. The rearrangement barriers significantly decrease due to the greater transfer of electron density from the catalytic metal center to the CO ligand oriented trans to the alkyne. This effect increases electrophilicity of the metal and lowers the calculated barriers by 9.0 kcal/mol. Subsequent evolution of the catalyst leads to the in situ formation of Rh(I) nanoclusters that catalyze stereoselective tautomerization. The intermediacy of heterogeneous catalysis by nanoclusters was confirmed by mercury poisoning, temperature-dependent sigmoidal kinetic curves, and dynamic light scattering. The combination of experiments and computations suggests that the initially formed allene-aldehyde product assists in the transformation of a homogeneous catalyst (or “a cocktail of catalysts”) into nanoclusters, which in turn catalyze and control the stereochemistry of subsequent transformations.
Co-reporter:Igor V. Alabugin, Stefan Bresch, and Mariappan Manoharan
The Journal of Physical Chemistry A 2014 Volume 118(Issue 20) pp:3663-3677
Publication Date(Web):April 28, 2014
DOI:10.1021/jp502472u
Trends in hybridization were systematically analyzed through the combination of DFT calculations with NBO analysis for the five elements X (X = B, C, N, O, and F) in 75 HnX–YHm compounds, where Y spans the groups 13–17 of the periods 2–4. This set of substrates probes the flexibility of the hybridization at five atoms X through variations in electronegativity, polarizability, and orbital size of Y. The results illustrate the scope and limitations of the Bent’s rule, the classic correlation between electronegativity and hybridization, commonly used in analyzing structural effects in carbon compounds. The rehybridization effects are larger for fluorine- and oxygen-bonds than they are in the similar bonds to carbon. For bonds with the larger elements Y of the lower periods, trends in orbital hybridization depend strongly on both electronegativity and orbital size. For charged species, the effects of substituent orbital size in the more polarizable bonds to heavier elements show a particularly strong response to the charge introduction at the central atom. In the final section, we provide an example of the interplay between hybridization effects with molecular structure and reactivity. In particular, the ability to change hybridization without changes in polarization provides an alternative way to control structure and reactivity, as illustrated by the strong correlation of strain in monosubstituted cyclopropanes with hybridization in the bond to the substituent.
Co-reporter:Sayantan Mondal, Brian Gold, Rana K. Mohamed, Hoa Phan, and Igor V. Alabugin
The Journal of Organic Chemistry 2014 Volume 79(Issue 16) pp:7491-7501
Publication Date(Web):July 10, 2014
DOI:10.1021/jo5012043
The switch from 5-exo- to 6-endo-trig selectivity in the radical cyclization of aromatic enynes was probed via the combination of experimental and computational methods. This transformation occurs by kinetic self-sorting of the mixture of four equilibrating radicals via 5-exo-trig cyclization, followed by homoallyl (3-exo-trig/fragmentation) ring expansion to afford the benzylic radical necessary for the final aromatizing C–C bond fragmentation. The interception of the intermediate 5-exo-trig product via β-scission of a properly positioned weak C–S bond provides direct mechanistic evidence for the 5-exo cyclization/ring expansion sequence. The overall cascade uses alkenes as synthetic equivalents of alkynes for the convenient and mild synthesis of Bu3Sn-functionalized naphthalenes.
Co-reporter:Rana K. Mohamed, Paul W. Peterson, and Igor V. Alabugin
Chemical Reviews 2013 Volume 113(Issue 9) pp:7089
Publication Date(Web):April 19, 2013
DOI:10.1021/cr4000682
Co-reporter:Paul W. Peterson, Nikolay Shevchenko, and Igor V. Alabugin
Organic Letters 2013 Volume 15(Issue 9) pp:2238-2241
Publication Date(Web):April 22, 2013
DOI:10.1021/ol400813d
The para-OMe functional group, usually regarded as a conjugative p-donor, acts as an efficient hyperconjugative σ-acceptor in reductive cycloaromatization reactions. This apparent reversal of electronic properties is associated with a conformational change that aligns the σ*O–C orbital with the adjacent aromatic system and provides stabilization to the developing negative charge in the TS of the dianionic cyclization of enediynes. The chameleonic character of the OMe group illustrates the important role of negative hyperconjugation in anionic processes.
Co-reporter:Dinesh V. Vidhani, Marie E. Krafft, and Igor V. Alabugin
Organic Letters 2013 Volume 15(Issue 17) pp:4462-4465
Publication Date(Web):August 22, 2013
DOI:10.1021/ol4019985
A novel Rh(I)-catalyzed approach to functionalized (E,Z) dienals has been developed via tandem transformation where a stereoselective hydrogen transfer follows a propargyl Claisen rearrangement. Z-Stereochemistry of the first double bond suggests the involvement of a six-membered cyclic intermediate whereas the E-stereochemistry of the second double bond stems from the subsequent protodemetalation step giving an (E,Z)-dienal.
Co-reporter:Sayantan Mondal, Rana K. Mohamed, Mariappan Manoharan, Hoa Phan, and Igor V. Alabugin
Organic Letters 2013 Volume 15(Issue 22) pp:5650-5653
Publication Date(Web):November 4, 2013
DOI:10.1021/ol4028072
Despite the possibility of intermolecular attack at four different locations, the Bu3Sn-mediated radical cyclization of aromatic enynes is surprisingly selective. The observed reaction path originates from the least stable of the equilibrating pool of isomeric radicals produced by intermolecular Bu3Sn attack at the π-bonds of substrates. The radical pool components are kinetically self-sorted via 5-exo-trig closure, the fastest of the four possible cyclizations. The resulting Sn-substituted indenes are capable of further transformations in reactions with electrophiles.
Co-reporter:Igor V. Alabugin and Kerry Gilmore
Chemical Communications 2013 vol. 49(Issue 96) pp:11246-11250
Publication Date(Web):17 Oct 2013
DOI:10.1039/C3CC43872D
Truly important scientific breakthroughs often come from catching the glimpses of order in chaos and distilling a large body of disjointed data into a clear set of simple concepts. Even more impressive is when the new conceptual framework is created with some of the keystones still missing. Such bold predictions, i.e. Mendeleev's eka-silicon, challenge and inspire, serving as powerful catalysts for scientific growth. The rules for ring closure formulated by Sir Jack Baldwin in 1976 constitute one of such bold intellectual advances. Baldwin developed a classification system that brought order to the chaos of possible cyclization patterns and suggested a set of rules to define the favourable modes of ring closure. Where sufficient data was lacking, particularly for the cyclizations of alkynes, Baldwin made testable predictions that challenged theoretical and experimental chemists. These guidelines have become the common starting point in the design of new cyclization reactions and catalyzed the development of modern stereoelectronic concepts.
Co-reporter:Dinesh V. Vidhani, John W. Cran, Marie E. Krafft and Igor V. Alabugin
Organic & Biomolecular Chemistry 2013 vol. 11(Issue 10) pp:1624-1630
Publication Date(Web):23 Nov 2012
DOI:10.1039/C2OB27231H
Computational and experimental analysis of unusual substituent effects in the Au-catalyzed propargyl Claisen rearrangement revealed new features important for the future development of Au(I) catalysis. Despite the higher stability of Au–alkyne complexes, they do not always correspond to the catalytically active compounds. Instead, the product emanates from the higher energy Au(I)–oxygen complex reacting via a low barrier cation-accelerated oxonia Claisen pathway. Additionally, both intra and intermolecular competition from other Lewis bases present in the system, for the Au(I) catalyst, can lead to unproductive stabilization of the substrate/catalyst complex, explaining hitherto unresolved substituent effects.
Co-reporter:Paul W. Peterson;Rana K. Mohamed
European Journal of Organic Chemistry 2013 Volume 2013( Issue 13) pp:2505-2527
Publication Date(Web):
DOI:10.1002/ejoc.201201656
Abstract
Cycloaromatization reactions decouple two electrons by breaking two π bonds to form only one σ bond and illustrate one of the most common mechanistic dichotomies in chemistry, namely the two ways of breaking a chemical bond: Zwitterionic or diradical. With a suitable choice of reaction conditions, substitution patterns, and catalysts, cycloaromatization processes can be redirected from the usual formation of a diradical towards a variety of zwitterionic pathways. This review illustrates the practical approaches for directing zwitterionic cycloaromatization reactions and lays the mechanistic foundations for the further development of this emerging field.
Co-reporter: Michael Shatruk; Igor V. Alabugin
Chemistry - A European Journal 2013 Volume 19( Issue 15) pp:4942-4945
Publication Date(Web):
DOI:10.1002/chem.201103017
Co-reporter:Denis S. Baranov, Brian Gold, Sergei F. Vasilevsky, and Igor V. Alabugin
The Journal of Organic Chemistry 2013 Volume 78(Issue 5) pp:2074-2082
Publication Date(Web):November 19, 2012
DOI:10.1021/jo302146r
The EtONa-mediated reaction of peri-R-ethynyl-9,10-anthraquinones with thiourea yields 2-R-7H-dibenzo[de,h]quinolin-7-ones and 2-R-anthra[2,1-b]thiophene-6,11-diones. Although 2-R-7H-dibenzo[de,h]quinolin-7-ones were observed previously in reactions with other N-centered nucleophiles (hydrazine, guanidine, and urea), the formation of 2-R-anthra[2,1-b]thiophene-6,11-diones is a new reactivity path. DFT computations analyzed factors responsible for the switch in reactivity and the relative importance of two possible pathways: (1) the “anchor-relay” mechanism mediated by nucleophilic attack at the carbonyl and (2) direct attack at the alkyne. The two pathways converge on a vinyl sulfur anion, set up for a 5-endo-trig cyclization at the ortho-position. Subsequent rearomatization/oxidation provides the fused thiophene product via formal C–H activation. The calculations suggest that the latter pathway, the direct attack at the alkyne, is more likely, due to the relatively high barrier for the 8-endo-dig cyclization (pathway 1). Computational insights led to a more selective synthesis of fused thiophenes, based on the reaction of acetylenic anthraquinones with sodium sulfide. This reaction does not require prefunctionalization at the ortho-position since direct C–H activation is efficient. The absence of fused five-membered heterocycles in earlier work was investigated computationally. The other N-centered nucleophiles form stronger anion−π complexes with the electron-deficient quinone core, promoting carbonyl attack over direct alkyne attack.
Co-reporter:Dinesh V. Vidhani, John W. Cran, Marie E. Krafft, Mariappan Manoharan, and Igor V. Alabugin
The Journal of Organic Chemistry 2013 Volume 78(Issue 5) pp:2059-2073
Publication Date(Web):November 20, 2012
DOI:10.1021/jo302152j
Curtin–Hammett analysis of four alternative mechanisms of the gold(I)-catalyzed [3,3] sigmatropic rearrangement of allenyl vinyl ethers by density functional theory calculations reveals that the lowest energy pathway (cation-accelerated oxonia Claisen rearrangement) originates from the second most stable of the four Au(I)-substrate complexes in which gold(I) coordinates to the lone pair of oxygen. This pathway proceeds via a dissociative transition state where the C–O bond cleavage precedes C1–C6 bond formation. The alternative Au(I) coordination at the vinyl π-system produces a more stable but less reactive complex. The two least stable modes of coordination at the allenyl π-system display reactivity that is intermediate between that of the Au(I)–oxygen and the Au(I)–vinyl ether complexes. The unusual electronic features of the four potential energy surfaces (PESs) associated with the four possible mechanisms were probed with intrinsic reaction coordinate calculations in conjunction with nucleus independent chemical shift (NICS(0)) evaluation of aromaticity of the transient structures. The development of aromatic character along the “6-endo” reaction path is modulated via Au-complexation to the extent where both the cyclic intermediate and the associated fragmentation transition state do not correspond to stationary points at the reaction potential energy surface. This analysis explains why the calculated PES for cyclization promoted by coordination of gold(I) to allenyl moiety lacks a discernible intermediate despite proceeding via a highly asynchronous transition state with characteristics of a stepwise “cyclization-mediated” process. Although reaction barriers can be strongly modified by aryl substituents of varying electronic demand, direct comparison of experimental and computational substituent effects is complicated by formation of Au-complexes with the Lewis-basic sites of the substrates.
Co-reporter:Igor V. Alabugin and Brian Gold
The Journal of Organic Chemistry 2013 Volume 78(Issue 16) pp:7777-7784
Publication Date(Web):July 5, 2013
DOI:10.1021/jo401091w
Spatial orthogonality of the two independently addressable π-systems in alkynes can be used for the design and control of metal-free cascade transformations. Examples include ionic chemistry of neutral hydrocarbons, preparation of radicals without radical initiators, generation of excited states without light, “1,2-dicarbene reactivity” of alkynes in “boomerang” radical processes, selective conversion of alkynes into carbonyl compounds, and full disassembly of the alkyne moiety.
Co-reporter:Philip M. Byers
Journal of the American Chemical Society 2012 Volume 134(Issue 23) pp:9609-9614
Publication Date(Web):May 23, 2012
DOI:10.1021/ja3023626
Selective radical generation in conjugated oligomeric o-aryleneethynylenes initiates an intramolecular cascade which involves five fast radical cyclizations followed by aromatization via a 1,5-H shift with a >93% yield per step. This radical cascade transformation opens a new avenue for the systematic and controlled preparation of functionalized graphene nanoribbons where, potentially, each of the peripheral aromatic rings can be different.
Co-reporter:Kerry Gilmore ; Mariappan Manoharan ; Judy I-Chia Wu ; Paul v. R. Schleyer
Journal of the American Chemical Society 2012 Volume 134(Issue 25) pp:10584-10594
Publication Date(Web):May 18, 2012
DOI:10.1021/ja303341b
The transition states (TSs) of 5-endo-dig and 5-endo-trig anionic ring closures are the first unambiguous examples of nonpericyclic reactions with TSs stabilized by aromaticity. Their five-center, six-electron in-plane aromaticity is revealed by the diatropic dissected nucleus-independent chemical shifts, −24.1 and −13.7 ppm, respectively, resulting from the delocalization of the lone pair at the nucleophilic center, a σ CC bond, and an in-plane alkyne (or alkene) π bond. Other seemingly analogous exo and endo cyclization TSs do not have these features. A symmetry-enhanced combination of through-space and through-bond interactions explains the anomalous geometric, energetic, and electronic features of the 5-endo ring closure transition state. Anionic 5-endo cyclizations can be considered to be “aborted” [2,3]-sigmatropic shifts. The connection between anionic cyclizations and sigmatropic shifts offers new possibilities for the design and electronic control of anionic isomerizations.
Co-reporter:Philip M. Byers, Julian I. Rashid, Rana K. Mohamed, and Igor V. Alabugin
Organic Letters 2012 Volume 14(Issue 23) pp:6032-6035
Publication Date(Web):November 28, 2012
DOI:10.1021/ol302922t
The Sonogashira/5-endo-dig/6-endo-dig cascade fuses a polycyclic aromatic backbone to the electron-rich furan subunit. The transformation proceeds in modest yields as a one-pot reaction. Efficiency of the full cascade is increased by removal of base prior to the addition of gold catalyst. Under these conditions, conversion to the full cascade products is achieved in nearly quantitative yields without purification of the intermediate products. Extension of the cascade toward triynes opens access to benzofuran-fused chrysene derivatives.
Co-reporter:Boris Breiner, Kemal Kaya, Saumya Roy, Wang-Yong Yang and Igor V. Alabugin
Organic & Biomolecular Chemistry 2012 vol. 10(Issue 20) pp:3974-3987
Publication Date(Web):07 Mar 2012
DOI:10.1039/C2OB00052K
Hybrid agents which combine potent DNA-photocleavers with tunable amino acids or small peptides were designed to improve selectivity of Nature's most potent class of antibiotics towards cancer cells. The ability of these compounds to photocleave DNA is controlled by their incorporation into hybrid architectures with functional elements derived from natural amino acids. These conjugates are highly effective at inducing double-strand DNA cleavage and, in some cases, rival or even surpass both naturally occurring DNA cleavers and anticancer agents that are currently in clinical use. The possibility of triggering their activity in a photochemical and pH-sensitive fashion allows for a high degree of selectivity over activation. The conjugates were shown to penetrate cell membranes and induce efficient intracellular DNA cleavage. Initial in vitro tests against a variety of cancer cell lines confirm the potential of these compounds as anticancer agents at low nanomolar concentrations.
Co-reporter:Sergei F. Vasilevsky;Brian Gold;Tatyana F. Mikhailovskaya
Journal of Physical Organic Chemistry 2012 Volume 25( Issue 11) pp:998-1005
Publication Date(Web):
DOI:10.1002/poc.2990
Independent of the nature of alkyne substitution, hydrazides of 4-arylethynyl-5-carboxylic acid annealed at the pyrazole scaffold undergo a regioselective base-catalyzed 6-endo-dig cyclization with the formation of pyrazolo[3,4-c]pyridine-7-ones. This behavior contrasts the observation of selective 5-exo closures in the analogous benzannelated systems and illustrates selective destabilization of the reaction path leading to the formation of a smaller ring. Computational analysis also reveals an important role of prototropic equilibria in rendering the overall cyclization feasible in the strained heterocyclic systems. The switch to the formation of a larger cycle suggests that strategic incorporation of strain can be used as a tool for the efficient control of regiochemistry of nucleophilic cyclizations. Copyright © 2012 John Wiley & Sons, Ltd.
Co-reporter:Brian Gold, Nikolay E. Shevchenko, Natalie Bonus, Gregory B. Dudley, and Igor V. Alabugin
The Journal of Organic Chemistry 2012 Volume 77(Issue 1) pp:75-89
Publication Date(Web):November 11, 2011
DOI:10.1021/jo201434w
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.
Co-reporter:Kerry Gilmore and Igor V. Alabugin
Chemical Reviews 2011 Volume 111(Issue 11) pp:6513
Publication Date(Web):August 23, 2011
DOI:10.1021/cr200164y
Co-reporter:Igor V. Alabugin ; Kerry Gilmore ;Mariappan Manoharan
Journal of the American Chemical Society 2011 Volume 133(Issue 32) pp:12608-12623
Publication Date(Web):June 15, 2011
DOI:10.1021/ja203191f
This work reexamined the stereoelectronic basis for the “favored attack trajectories” regarding the nucleophilic and radical cyclizations of alkynes. In contrast to the original Baldwin rules, the acute attack angle of a nucleophile leading to the proposed endo-dig preference for the formation of small cycles is less favorable stereoelectronically than the alternative obtuse trajectory leading to the formation of exo-dig products. For smaller cycles, this intrinsic stereoelectronic preference can be masked by the greater thermodynamic stability of the less strained endo-products. Unbiased comparison of competing cyclization attacks has been accomplished via dissection of the activation barrier into the intrinsic barrier and thermodynamic component via Marcus theory. Intrinsic barriers of thermoneutral reactions strongly favor exo-dig closures, in full accord with the greater magnitude of two-electron bond forming interactions for the obtuse trajectory. This analysis agrees very well with experimental observations of efficient 3-exo-dig and 4-exo-dig cyclizations predicted to be unfavorable by the Baldwin rules and with the calculated 3-exo-/4-endo-, 4-exo-/5-endo-, and 5-exo-/6-endo-dig selectivities in the cyclizations of carbon-, nitrogen-, and oxygen-centered nucleophiles. The generality of these predictions is confirmed by analogous trends for the related radical cyclizations where the stereoelectronically favorable exo-closures are also preferred kinetically, with a few exceptions where a large difference in product stability skews the intrinsic stereoelectronic trends.
Co-reporter:Wang-Yong Yang ; Saumya Roy ; Boondaniwon Phrathep ; Zach Rengert ; Rachael Kenworthy ; Diego A. R. Zorio
Journal of Medicinal Chemistry 2011 Volume 54(Issue 24) pp:8501-8516
Publication Date(Web):November 3, 2011
DOI:10.1021/jm2010282
We describe a family of hybrid compounds for the most efficient light-activated double-strand (ds) DNA cleavage known to date. This family represents the second generation of “switchable” molecular systems for pH-gated ds DNA-cleavage which combine a potent DNA-photocleaver and a pH-regulated part derived from a dipeptide. Design of the pH-switchable part utilizes amino groups of different basicity. Whereas the basic amino groups are protonated throughout the biologically relevant pH range, the pH-gating amines undergo protonation at the pH threshold which separates cancer and normal cells. Control over the reactivity and selectivity is achieved via transformation of the initial protonation state (a monocation or a dication) into a trication at the acidic pH. This change leads to an extraordinary increase in the efficiency of ds DNA cleavage leading to the ds:ss ratios comparable with the most efficient nonenzymatic ds DNA cleavers. Statistical analysis reveals that these high ds:ss ratios result from the combination of several factors: (a) true double-stranded cleavage, and (b) conversion of single-stranded (ss)-scission into ds cleavage. Considerable part of ds cleavage is also produced via the combination of ss cleavage events.
Co-reporter:Denis S. Baranov, Sergei F. Vasilevsky, Brian Gold and Igor V. Alabugin
RSC Advances 2011 vol. 1(Issue 9) pp:1745-1750
Publication Date(Web):25 Oct 2011
DOI:10.1039/C1RA00622C
Molten urea serves both as a solvent and a reagent for the one-pot addition/cyclizations/fragmentation cascade which converts peri-alkynyl-9,10-anthraquinones into 2-R-7H-dibenzo[de,h]quinolin-7-ones – substituted analogues of Aporphinoid alkaloids.
Co-reporter:Sergey F. Vasilevsky, Anastasiya I. Govdi, Irina V. Sorokina, Tatyana G. Tolstikova, Dmitry S. Baev, Genrikh A. Tolstikov, Victor I. Mamatuyk, Igor V. Alabugin
Bioorganic & Medicinal Chemistry Letters 2011 Volume 21(Issue 1) pp:62-65
Publication Date(Web):1 January 2011
DOI:10.1016/j.bmcl.2010.11.072
Plant-derived pentacyclic triterpenoids of lupane and oleanane families provide a versatile structural platform for the discovery of new biologically active compounds. A number of semisynthetic derivatives of these molecules, possess high medical efficiency including antiviral (HIV-1), anticancer and immunomodulating activity. Even small structural changes in these triterpenoid derivatives were reported to lead to significant changes in their activity, making a convincing case for a systematic study of structure–activity relationships in this class of compounds.Our earlier work opened synthetic access to alkynes derived from the betulonic scaffold and enabled the development of a new family of biohybrids using Click Chemistry (CC). The computer-aided prediction of several types of biological activity were performed with program PASS (Prediction Activity Spectra of Substances. Experimental studies based on mouse models verified the SAR predictions obtained by the PASS program. The observed correlation between the anti-inflammatory and antioxidant activity indicates substantial contribution of the latter in the mechanism of anti-inflammatory effect of the triazole derivatives of betulonic acid.
Co-reporter:Abdulkader Baroudi, Jeremiah Alicea, Phillip Flack, Jason Kirincich, and Igor V. Alabugin
The Journal of Organic Chemistry 2011 Volume 76(Issue 6) pp:1521-1537
Publication Date(Web):February 23, 2011
DOI:10.1021/jo102467j
We report a metal-free procedure for transformation of phenols into esters and amides of benzoic acids via a new radical cascade. Diaryl thiocarbonates and thiocarbamates, available in a single high-yielding step from phenols, selectively add silyl radicals at the sulfur atom of the C═S moiety. This addition step, analogous to the first step of the Barton−McCombie reaction, produces a carbon radical which undergoes 1,2 O→C transposition through an O-neophyl rearrangement. The usually unfavorable equilibrium in the reversible rearrangement step is shifted forward via a highly exothermic C−S bond scission in the O-centered radical, which furnishes the final benzoic ester or benzamide product. The metal-free preparation of benzoic acid derivatives from phenols provides a potentially useful alternative to metal-catalyzed carbonylation of aryl triflates.
Co-reporter:A. A. Stepanov, L. M. Gornostaev, S. F. Vasilevsky, E. V. Arnold, V. I. Mamatyuk, D. S. Fadeev, B. Gold, and I. V. Alabugin
The Journal of Organic Chemistry 2011 Volume 76(Issue 21) pp:8737-8748
Publication Date(Web):September 12, 2011
DOI:10.1021/jo2014214
The nature of products in the diazotization of 1-amino-2-acetylenyl-9,10-anthraquinones strongly depends on the nature of substituents at both the alkyne and at the anthraquinone core. Donor substitution (NHAr, OH) at the fourth position stabilizes the diazonium salt at C1, decelerating electrophilic cyclization at the arylethynyl substituent at C2. This effect allows the replacement of the diazonium with azide group and subsequent closure into isoxazole ring with preservation of the alkyne. In contrast, electrophilic 5-exo-dig cyclizations to condensed pyrazoles is observed for the combination of donor substituents at the aryl alkyne moiety and an OAc substituent at C4. The latter process provides a new synthetic route to 3-ethynyl-[1,9-cd]isoxazol-6-ones that are difficult to access otherwise. DFT calculations suggest that donor substituents have only a minor effect on alkyne and diazonium polarization in the reactant but provide specific transition state stabilization by stabilizing the incipient vinyl cation. This analysis provides the first computational data on electrophilic 5-exo-dig cyclization in its parent form and the nucleophile-promoted version. This cyclization is a relatively fast but endothermic process that is rendered thermodynamically feasible by the enol-keto tautomerization with concomitant aromatization in the five-membered heteroaromatic ring. Computations suggest that the importance of nucleophilic assistance in the transition state for a relatively weak nucleophile such as water is minor because the energy gain due to the Lewis base coordination to the carbocationic center is more than compensated for by the unfavorable entropic term for the bimolecular proces.
Co-reporter:Saumya Roy, Maria P. Davydova, Runa Pal, Kerry Gilmore, Genrikh A. Tolstikov, Sergei F. Vasilevsky, and Igor V. Alabugin
The Journal of Organic Chemistry 2011 Volume 76(Issue 18) pp:7482-7490
Publication Date(Web):August 1, 2011
DOI:10.1021/jo201259j
The reaction of diaryl ketoalkynes with 1,2-diamino ethane leads to the full scission of the triple bond with the formation of acetophenone and imidazoline fragments. In this transformation, one of the alkyne carbons undergoes formal reduction with the formation of three C–H bonds, whereas the other carbon undergoes formal oxidation via the formation of three C–N bonds (one π and two σ). Computational analysis confirmed that the key fragmentation step proceeds via a six-membered TS in a concerted manner. Both amines are involved in the fragmentation: the N–H moiety of one amine transfers a proton to the developing negative charge at the enolate oxygen, while the other amine provides direct stereoelectronic assistance to the C–C bond cleavage via a hyperconjugative nN → σ*C–C interaction.
Co-reporter:Igor V. Alabugin;Brian Gold;Michael Shatruk;Kirill Kovnir
Science 2010 Vol 330(6007) pp:1047
Publication Date(Web):19 Nov 2010
DOI:10.1126/science.1196188
Abstract
Legrand et al. (Reports, 16 July 2010, p. 299) reported the experimental observation of square-planar and rectangular-bent geometries of 1,3-dimethylcyclobutadiene (Me2CBD) confined within a crystalline matrix. However, we found no evidence for the Me2CBD formation. We argue that the experimental x-ray density data are better attributed to the bicyclic β-lactone intermediate where carbon dioxide is covalently bound to cyclobutadiene.
Co-reporter:Abdulkader Baroudi;Phillip Flack ; Igor V. Alabugin
Chemistry - A European Journal 2010 Volume 16( Issue 41) pp:12316-12320
Publication Date(Web):
DOI:10.1002/chem.201002303
Co-reporter:Runa Pal, Ronald J. Clark, Mariappan Manoharan, and Igor V. Alabugin
The Journal of Organic Chemistry 2010 Volume 75(Issue 24) pp:8689-8692
Publication Date(Web):November 23, 2010
DOI:10.1021/jo101838a
Fast anionic oxy-Cope rearrangements of 1,5-hexadiyn-3,4-olates can be incorporated into cascade transformations which rapidly assemble densely functionalized cyclobutenes or cyclopentenones via a common bis-allenic intermediate. The competition between fragmentation, 4π-electrocyclic closure, and aldol condensation can be efficiently controlled by the nature of the acetylenic substituents. The rearrangement of bis-alkynes with two hydroxyl substituents opens a conceptually interesting entry in the chemistry of ε-dicarbonyl compounds and suggests a new approach to analogues of rocaglamide/aglafolin.
Co-reporter:Abdulkader Baroudi;Jeremiah Alicea ;IgorV. Alabugin Dr.
Chemistry - A European Journal 2010 Volume 16( Issue 26) pp:7683-7687
Publication Date(Web):
DOI:10.1002/chem.201001056
Co-reporter:Abdulkader Baroudi ; Justin Mauldin
Journal of the American Chemical Society 2009 Volume 132(Issue 3) pp:967-979
Publication Date(Web):December 30, 2009
DOI:10.1021/ja905100u
A variety of fragmentations and rearrangements can follow Bergman cyclization in enediynes equipped with acetal rings mimicking the carbohydrate moiety of natural enediyne antibiotics of the esperamicine and calchiamicine families. In the first step of all these processes, intramolecular H-atom abstraction efficiently intercepts the p-benzyne product of the Bergman cyclization through a six-membered TS and transforms the p-benzyne into a new more stable radical. Depending on the substitution pattern and reaction conditions, this radical follows four alternative paths: (a) abstraction of an external hydrogen atom, (b) O-neophyl rearrangement which transposes O- and C-atoms of the substituent, (c) fragmentation of the O−C bond in the acetal ring, or (d) fragmentation with elimination of the appended acetal moiety as a whole. Experiments with varying concentrations of external H-atom donor (1,4-cyclohexadiene) were performed to gain further insight into the competition between intermolecular H-abstraction and the fragmentations. The Thorpe−Ingold effect in gem-dimethyl substituted enediynes enhances the efficiency of fragmentation to the extent where it cannot be prevented even by a large excess of external H-atom donor. These processes provide insight into a possible mechanism of unusual fragmentation of esperamicin A1 upon its Bergman cycloaromatization and lay foundation for a new approach for the conformational control of reactivity of these natural antitumor antibiotics. Such an approach, in conjunction with supramolecular constraints, may provide a plausible mechanism for resistance to enediyne antibiotics by the enediyne-producing microorganisms.
Co-reporter:Sergey F. Vasilevsky, Anastasiya I. Govdi, El’vira E. Shults, Makhmut M. Shakirov, Irina V. Sorokina, Tatyana G. Tolstikova, Dmitry S. Baev, Genrikh A. Tolstikov, Igor V. Alabugin
Bioorganic & Medicinal Chemistry 2009 Volume 17(Issue 14) pp:5164-5169
Publication Date(Web):15 July 2009
DOI:10.1016/j.bmc.2009.05.059
The Sonogashira reaction can be applied for the preparation of acetylenic derivatives of betulonic acid where the triterpenoid moiety can serve as either the halo- or the acetylenic component. This reaction opened access to the first derivatives of betulonic acid containing either the arylethynyl (СС-Ar(Het) or the ethynyl (ССН) moieties. From the fundamental perspective, this work illustrates the possibility of selective Pd-catalyzed cross-coupling at terminal acetylenes in the presence of a terminal alkene. Hepatoprotective and anti-inflammatory properties of selected acetylenic derivatives of betulonic acid were investigated using the CCl4-induced hepatitis and carrageenan-induced edema models, respectively.
Co-reporter:Sergei F. Vasilevsky, Denis S. Baranov, Victor I. Mamatyuk, Yury V. Gatilov and Igor V. Alabugin
The Journal of Organic Chemistry 2009 Volume 74(Issue 16) pp:6143-6150
Publication Date(Web):July 8, 2009
DOI:10.1021/jo9008904
This work analyzes multiple new reaction pathways which originate from intramolecular reactions of activated alkynes with the appropriately positioned multifunctional hemiaminal moiety. Combination of experimental substituent effects with Natural Bond Orbital (NBO) analysis revealed that alkyne polarization controls partitioning between these cascades. A particularly remarkable transformation leads to the formation of six new bonds at the two alkyne carbons due to complete disassembly of the alkyne moiety and formal insertion of a nitrogen atom between the two acetylenic carbons of the reactant. This reaction offers a new synthetic approach for the preparation of polycyclic aromatic amides with a number of possible applications in molecular electronics. Another of the newly discovered cascades opens access to substituted analogues of Sampangine alkaloids which are known for their antifungal and antimycobacterial activity against AIDS-related opportunistic infection pathogens.
Co-reporter:Boris Breiner;Jörg C. Schlatterer;Serguei V. Kovalenko;Nancy L. Greenbaum;
Proceedings of the National Academy of Sciences 2007 104(32) pp:13016-13021
Publication Date(Web):July 30, 2007
DOI:10.1073/pnas.0705701104
Simple lysine conjugates are capable of selective DNA damage at sites approximating a variety of naturally occurring DNA-damage
patterns. This process transforms single-strand DNA cleavage into double-strand cleavage with a potential impact on gene and
cancer therapy or on the design of DNA constructs that require disassembly at a specific location. This study constitutes
an example of DNA damage site recognition by molecules that are two orders of magnitude smaller than DNA-processing enzymes
and presents a strategy for site-selective cleavage of single-strand nucleotides, which is based on their annealing with two
shorter counterstrands designed to recreate the above duplex damage site.
Co-reporter:Igor V. Alabugin, Mariappan Manoharan, Matthew Buck, Ronald J. Clark
Journal of Molecular Structure: THEOCHEM 2007 Volume 813(1–3) pp:21-27
Publication Date(Web):1 July 2007
DOI:10.1016/j.theochem.2007.02.016
Efficient rehybridization at nitrogen provides a convenient conceptual framework for rationalizing structural and electronic effects in substituted anilines. Computations predict that a subtle balance between hybridization and conjugation in substituted anilines is easily perturbed by remote substitution. Rehybridization correlates with electronegativity of substituents as predicted by the Bent’s rule even though the substitution is not direct but mediated by an aromatic system. Use of the σ− Hammett parameters significantly improves the description of substituent effects. Limitations of X-ray crystallography in studies of subtle electronic structure effects are shown through comparison of computational geometries with crystallographic data which illustrates how supramolecular forces associated with the crystal packing mask intrinsic electronic preferences.
Co-reporter:Boris Breiner;Jörg C. Schlatterer;Serguei V. Kovalenko;Nancy L. Greenbaum Dr.
Angewandte Chemie 2006 Volume 118(Issue 22) pp:
Publication Date(Web):27 APR 2006
DOI:10.1002/ange.200504479
Kompromisse: Die Sequenzselektivität der DNA-Photospaltung durch Endiin-, Acetylen- und Fulven-Lysin-Konjugate wurde mithilfe markierter DNA-Oligomere untersucht. Da die angehängte 32P-Markierung durch diese Photospalter verloren ging, wurde sie an eine geschützte Stelle innerhalb des Oligomers positioniert (siehe Bild). Die Selektivität der Spaltung wird durch einen Kompromiss zwischen AT-Selektivität für die Bindung und G-Selektivität für den Elektronentransfer bestimmt.
Co-reporter:Boris Breiner;Jörg C. Schlatterer;Serguei V. Kovalenko;Nancy L. Greenbaum Dr.
Angewandte Chemie International Edition 2006 Volume 45(Issue 22) pp:
Publication Date(Web):27 APR 2006
DOI:10.1002/anie.200504479
Finding a compromise: The sequence selectivity of DNA photocleavage by enediyne–, acetylene–, and fulvene–lysine conjugates was investigated by using labeled DNA oligomers. Since the external 32P label was removed by these photocleavers, the label was protected by translocation inside the oligomer (see figure). The selectivity of cleavage is controlled by a compromise between AT selectivity for binding and G selectivity for electron transfer.
Co-reporter:Serguei V. Kovalenko and Igor V. Alabugin
Chemical Communications 2005 (Issue 11) pp:1444-1446
Publication Date(Web):25 Jan 2005
DOI:10.1039/B417012A
Statistical analysis of DNA-photocleavage by two types of lysine–enediyne conjugates confirms that more double-strand breaks are produced than can be accounted for by coincident single-strand breaks.
Co-reporter:Scott W. Peabody, Boris Breiner, Serguei V. Kovalenko, Satish Patil and Igor V. Alabugin
Organic & Biomolecular Chemistry 2005 vol. 3(Issue 2) pp:218-221
Publication Date(Web):14 Dec 2004
DOI:10.1039/B417493N
A facile enediyne→fulvene→indene transformation provides a route to all possible isotopomers of substituted fulvenes and indenes.
Co-reporter:Tarek A. Zeidan;Ronald J. Clark ;Ion Ghiviriga Dr.;Serguei V. Kovalenko Dr.
Chemistry - A European Journal 2005 Volume 11(Issue 17) pp:
Publication Date(Web):20 JUN 2005
DOI:10.1002/chem.200500180
1,5-Diaryl substituted homoquadricyclanes which are readily available through cascade photocycloaddition of diarylacetylenes to 1,4-cyclohexadienes are useful supramolecular scaffolds with an angle of about 60° formed by the two aromatic rings defining a hydrophobic cavity. These structural features of pyridinyl homoquadricyclanes were applied to the design of composite organic/inorganic materials with topologies depending on the ratio of ligand to metal. The crystal structure of complex 1 (L1/AgNO3 in a 1:1 ratio) shows an alternating ligand–metal polymer in which each of the silver ions in its linear coordination geometry is shared between two L1 molecules. A small change in the crystallization method yields a supramolecular rhomboid (complex 2, L1/AgNO3 3:2 ratio) which has two ligands that occupy opposite corners of the rhomboid and two silver atoms occupy the other two corners. Connection of the rhomboids units through a third molecule forms unique “beads on a string” polymeric chains. In complex 2, the silver ions adopt a distorted tetrahedral geometry with the nitrate anion occupying one of the vertices of the tetrahedron. The crystal packing of the chain of rhomboids generates cavities which are filled with disordered solvent molecules. Non-symmetrical homoquadricyclane L3 coordinates with silver only through the nitrogen of the pyridine ring but not through the nitrogen of the tetrafluoropyridine ring in which the electron density of the nitrogen lone-pair is very low. The substituents on the polycyclic moiety of the homoquadricyclane cause restricted rotation of the pyridine rings which suggests that the flexibility of such systems can be fine-tuned to create a family of supramolecular scaffolds of controlled rigidity.
Co-reporter:Brian Gold ; Gregory B. Dudley
Journal of the American Chemical Society () pp:
Publication Date(Web):December 31, 2012
DOI:10.1021/ja3114196
Recently, we have identified two strategies for selective transition state (TS) stabilization in catalyst-free azide/alkyne cycloadditions. In particular, the transition states for the formation of both 1,4- and 1,5-isomers can be stabilized via hyperconjugative assistance for the C···N bond formation, whereas the 1,5-TS can be stabilized via C–H···X H-bonding interactions. When the hyperconjugative assistance is maximized by the antiperiplanar arrangement of propargylic σ-acceptors relative to the forming bonds, the combination of these TS-stabilizing effects was predicted to lead to ∼1 million fold acceleration of the cycloaddition with methyl azide. The present work investigated whether hyperconjugative assistance and H-bonding can be combined with strain activation for the design of even more reactive alkynes and whether reactivity can be turned “on demand.” When stereoelectronic amplification is achieved by optimal positioning of σ-acceptors at the endocyclic bonds antiperiplanar to the breaking alkyne π-bonds, the stabilization of the bent alkyne geometry leads to a significant decrease in strain in cyclic alkynes without compromising their reactivity in alkyne–azide cycloadditions. The approach can be used in a modular fashion where the TS stabilizing effects are introduced sequentially until the desired level of reactivity is achieved. A significant increase in reactivity upon the protonation of an endocyclic NH-group suggests a new strategy for the design of click reactions triggered by a pH-change or introduction of an external Lewis acid.
Co-reporter:Gabriel dos Passos Gomes, Christopher J. Evoniuk, Michelle Ly and Igor V. Alabugin
Organic & Biomolecular Chemistry 2017 - vol. 15(Issue 19) pp:NaN4143-4143
Publication Date(Web):2017/04/03
DOI:10.1039/C7OB00527J
Chemoselective addition of radicals to isonitriles can be harnessed for initiating reaction cascades designed to overcome the stereoelectronic restrictions on homoallylic ring expansion in alkyne reactions and to develop a new general route for the preparation of N-heteroaromatics. This method utilizes alkenes as synthetic equivalents of alkynes by coupling homoallylic ring expansion to yield the formal “6-endo” products with aromatization via stereoelectronically assisted C–C bond scission. Detailed computational analysis of the individual steps of the homoallylic expansion sequence maps effects of substituents and structural constraints on this multi-step potential energy surface.
Co-reporter:Christopher J. Evoniuk, Sean P. Hill, Kenneth Hanson and Igor V. Alabugin
Chemical Communications 2016 - vol. 52(Issue 44) pp:NaN7141-7141
Publication Date(Web):2016/05/04
DOI:10.1039/C6CC03106D
A new method for intramolecular C–H oxidative amination is based on a FeCl3-mediated oxidative reaction of anilines with activated sp3 C–H bonds. The amino group plays multiple roles in the reaction cascade: (1) as the activating group in single-electron-transfer (SET) oxidation process, (2) as a directing group in benzylic/allylic C–H activation at a remote position, and (3) internal nucleophile trapping reactive intermediates formed from the C–H activation steps. These multielectron oxidation reactions proceed with catalytic amounts of Fe(III) and inexpensive reagents.
Co-reporter:Christopher J. Evoniuk, Michelle Ly and Igor V. Alabugin
Chemical Communications 2015 - vol. 51(Issue 64) pp:NaN12834-12834
Publication Date(Web):2015/07/08
DOI:10.1039/C5CC04391C
Stereoelectronic restrictions on homoallylic ring expansion in alkyne cascades can be overcome by using alkenes as synthetic equivalents of alkynes in reaction cascades that are terminated by C–C bond fragmentation. Implementation of this approach using Mn(III)-mediated reaction of o-alkenyl isocyanides and boronic acids leads to efficient synthesis of substituted quinolines.
Co-reporter:Gabriel dos Passos Gomes, Vera Vil', Alexander Terent'ev and Igor V. Alabugin
Chemical Science (2010-Present) 2015 - vol. 6(Issue 12) pp:NaN6791-6791
Publication Date(Web):2015/09/07
DOI:10.1039/C5SC02402A
The unusual stability of bis- and tris-peroxides contradicts the conventional wisdom – some of them can melt without decomposition at temperatures exceeding 100 °C. In this work, we disclose a stabilizing stereoelectronic effect that two peroxide groups can exert on each other. This stabilization originates from strong anomeric nO → σ*CO interactions that are absent in mono-peroxides but reintroduced in molecules where two peroxide moieties are separated by a CH2 group. Furthermore, such effects can be induced by other σ-acceptors and amplified by structural constraints imposed by cyclic and bicyclic frameworks.
Co-reporter:Dinesh V. Vidhani, John W. Cran, Marie E. Krafft and Igor V. Alabugin
Organic & Biomolecular Chemistry 2013 - vol. 11(Issue 10) pp:NaN1630-1630
Publication Date(Web):2012/11/23
DOI:10.1039/C2OB27231H
Computational and experimental analysis of unusual substituent effects in the Au-catalyzed propargyl Claisen rearrangement revealed new features important for the future development of Au(I) catalysis. Despite the higher stability of Au–alkyne complexes, they do not always correspond to the catalytically active compounds. Instead, the product emanates from the higher energy Au(I)–oxygen complex reacting via a low barrier cation-accelerated oxonia Claisen pathway. Additionally, both intra and intermolecular competition from other Lewis bases present in the system, for the Au(I) catalyst, can lead to unproductive stabilization of the substrate/catalyst complex, explaining hitherto unresolved substituent effects.
Co-reporter:Boris Breiner, Kemal Kaya, Saumya Roy, Wang-Yong Yang and Igor V. Alabugin
Organic & Biomolecular Chemistry 2012 - vol. 10(Issue 20) pp:NaN3987-3987
Publication Date(Web):2012/03/07
DOI:10.1039/C2OB00052K
Hybrid agents which combine potent DNA-photocleavers with tunable amino acids or small peptides were designed to improve selectivity of Nature's most potent class of antibiotics towards cancer cells. The ability of these compounds to photocleave DNA is controlled by their incorporation into hybrid architectures with functional elements derived from natural amino acids. These conjugates are highly effective at inducing double-strand DNA cleavage and, in some cases, rival or even surpass both naturally occurring DNA cleavers and anticancer agents that are currently in clinical use. The possibility of triggering their activity in a photochemical and pH-sensitive fashion allows for a high degree of selectivity over activation. The conjugates were shown to penetrate cell membranes and induce efficient intracellular DNA cleavage. Initial in vitro tests against a variety of cancer cell lines confirm the potential of these compounds as anticancer agents at low nanomolar concentrations.
Co-reporter:Igor V. Alabugin and Kerry Gilmore
Chemical Communications 2013 - vol. 49(Issue 96) pp:NaN11250-11250
Publication Date(Web):2013/10/17
DOI:10.1039/C3CC43872D
Truly important scientific breakthroughs often come from catching the glimpses of order in chaos and distilling a large body of disjointed data into a clear set of simple concepts. Even more impressive is when the new conceptual framework is created with some of the keystones still missing. Such bold predictions, i.e. Mendeleev's eka-silicon, challenge and inspire, serving as powerful catalysts for scientific growth. The rules for ring closure formulated by Sir Jack Baldwin in 1976 constitute one of such bold intellectual advances. Baldwin developed a classification system that brought order to the chaos of possible cyclization patterns and suggested a set of rules to define the favourable modes of ring closure. Where sufficient data was lacking, particularly for the cyclizations of alkynes, Baldwin made testable predictions that challenged theoretical and experimental chemists. These guidelines have become the common starting point in the design of new cyclization reactions and catalyzed the development of modern stereoelectronic concepts.
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![Benzene, 1-bromo-2-[2-(4-methylphenyl)ethynyl]-](/data/chemimg/3740700/38175-73-4_b.png)
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![1H-Indene,1-[(4-methoxyphenyl)methylene]-](http://img.cochemist.com/ccimg/2500/2428-41-3_b.png)
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