Co-reporter:Yijie Niu, Ning Wang, Alberto Muñoz, Jiahui Xu, Hao Zeng, Tomislav Rovis, and Jeehiun K. Lee
Journal of the American Chemical Society October 25, 2017 Volume 139(Issue 42) pp:14917-14917
Publication Date(Web):October 17, 2017
DOI:10.1021/jacs.7b05229
In recent years, triazolylidene carbenes have come to the forefront as important organocatalysts for a wide range of reactions. The fundamental properties of these species, however, remain largely unknown. Herein, the gas phase acidities have been measured and calculated for a series of triazolium cations (the conjugate acids of the triazolylidene carbenes) that have not been heretofore examined in vacuo. The results are discussed in the context of these species as catalysts. We find correlations between the gas phase acidity and selectivity in two Umpolung reactions catalyzed by these species; such correlations are the first of their kind. We are able to use these linear correlations to improve reaction enantioselectivity. These results establish the possibility of using these thermochemical properties to predict reactivity in related transformations.
Co-reporter:Dr. G. S. M. Kiruba;Jiahui Xu;Victoria Zelikson ;Dr. Jeehiun K. Lee
Chemistry - A European Journal 2016 Volume 22( Issue 11) pp:3881-3890
Publication Date(Web):
DOI:10.1002/chem.201505003
Abstract
Gas-phase thermochemical properties (tautomerism, acidity, and proton affinity) have been measured and calculated for a series of nucleobase derivatives that have not heretofore been examined under vacuum. The studied species are substrates for the enzyme formamidopyrimidine glycosylase (Fpg), which cleaves damaged nucleobases from DNA. The gas-phase results are compared and contrasted to solution-phase data, to afford insight into the Fpg mechanism. Calculations are also used to probe the energetics of various possible mechanisms and to predict isotope effects that could potentially allow for discrimination between different mechanisms. Specifically, 18O substitution at the ribose O4′ is predicted to result in a normal kinetic isotope effect (KIE) for a ring-opening “endocyclic” mechanism and an inverse KIE for a direct base excision “exocyclic” pathway.
Co-reporter:Hao Zeng, Kai Wang, Yuan Tian, Yijie Niu, Landon Greene, Zhichao Hu, Jeehiun K. Lee
International Journal of Mass Spectrometry 2015 Volume 378() pp:169-174
Publication Date(Web):15 February 2015
DOI:10.1016/j.ijms.2014.07.043
•We have synthesized a novel charge-tagged N-heterocyclic carbene (thiazolylidene).•Sulfonate-tagged thiazolylidene was used to catalyze the umpolung benzoin condensation.•Sulfonate-tagged catalyst was also used to fish out reaction intermediates for MS detection.•Results support Breslow, not dimer mechanism for benzoin condensation.A novel thiazolium with a sulfonate charge tag was synthesized to test the feasibility of tracking the progress of a thiazolylidene-catalyzed benzoin condensation reaction using electrospray ionization-mass spectrometry (ESI–MS). Intermediates in the benzoin condensation were “fished” out of a reaction mixture and detected using MS. Tandem MS and calculations were used to support structural assignments. The results are consistent with the Breslow mechanism. These data show the viability of synthesizing negatively charged compounds that will both catalyze and track reactions involving N-heterocyclic carbene organocatalysis, which are becoming increasingly prevalent in organic synthesis.
Co-reporter:Yuan Tian and Jeehiun K. Lee
The Journal of Organic Chemistry 2015 Volume 80(Issue 13) pp:6831-6838
Publication Date(Web):June 12, 2015
DOI:10.1021/acs.joc.5b01069
N-Heterocyclic carbenes (NHCs) catalyze Umpolung condensation reactions of carbonyl compounds, including the Stetter reaction. These types of reactions have not heretofore been examined in the gas phase. Herein, we explore the feasibility of examining these reactions in the absence of solvent. A charge-tagged thiazolylidene catalyst is used to track the reactions by mass spectrometry. We find that the first Umpolung step, the addition of the NHC catalyst to a carbonyl compound to form the “Breslow intermediate”, does not readily proceed in the gas phase, contrary to the case in solution. The use of acylsilanes in place of the carbonyl compounds appears to solve this issue, presumably because of a favorable Brook rearrangement. The second addition reaction, with enones, does not occur under our gas phase conditions. These reactions do occur in solution; the differential reactivity between the condensed and gas phases is discussed, and calculations are used to aid in the interpretation of the results.
Co-reporter:Hao Zeng, Kai Wang, Yuan Tian, Yijie Niu, Landon Greene, Zhichao Hu, Jeehiun K. Lee
International Journal of Mass Spectrometry 2014 Volume 369() pp:92-97
Publication Date(Web):15 August 2014
DOI:10.1016/j.ijms.2014.06.008
•We have synthesized a novel charge-tagged N-heterocyclic carbene (thiazolylidene).•Sulfonate-tagged thiazolylidene was used to catalyze the umpolung benzoin condensation.•Sulfonate-tagged catalyst was also used to fish out reaction intermediates for MS detection.•Results support Breslow, not dimer mechanism for benzoin condensation.A novel thiazolium with a sulfonate charge tag was synthesized to test the feasibility of tracking the progress of a thiazolylidene-catalyzed benzoin condensation reaction using electrospray ionization-mass spectrometry (ESI–MS). Intermediates in the benzoin condensation were “fished” out of a reaction mixture and detected using MS. Tandem MS and calculations were used to support structural assignments. The results are consistent with the Breslow mechanism. These data show the viability of synthesizing negatively charged compounds that will both catalyze and track reactions involving N-heterocyclic carbene organocatalysis, which are becoming increasingly prevalent in organic synthesis.
Co-reporter:Mu Chen and Jeehiun K. Lee
The Journal of Organic Chemistry 2014 Volume 79(Issue 23) pp:11295-11300
Publication Date(Web):November 7, 2014
DOI:10.1021/jo502058w
In this Synopsis, we highlight some recent computational studies of the gas-phase thermochemical properties of modified nucleobases. Although this field is relatively nascent, we aim herein to show a few examples of insights that have already been gained by gas-phase calculations. We focus on modified nucleobases that are substrates for enzymes that excise damaged bases from DNA. Because these enzymes have hydrophobic active sites, calculations in the “ultimate” nonpolar environment of the gas phase prove to be particularly relevant, providing insight into enzyme mechanism.
Co-reporter:Mu Chen, Jonathan P. Moerdyk, Garrett A. Blake, Christopher W. Bielawski, and Jeehiun K. Lee
The Journal of Organic Chemistry 2013 Volume 78(Issue 20) pp:10452-10458
Publication Date(Web):October 3, 2013
DOI:10.1021/jo401902c
The gas-phase proton affinities (PAs) of a series of novel diamidocarbenes (DACs) were assessed and compared to various imidazolylidene-based N-heterocyclic carbenes (NHCs) through experimental and computational methods. Apart from a perfluorinated-phenyl derivative (PA = 233 kcal/mol), the calculated and measured PAs for a range of DACs (256–261 kcal/mol) were comparable to those of the NHCs (260–266 kcal/mol). Proton transfer from the protonated carbene to various reference bases, as observed by mass spectrometry, was inhibited by steric bulk and precluded the direct measurement of the PA for the known DACs, N,N′-dimesityl-4,6-diketo-5,5-dimethylpyrimidin-2-ylidene and N,N′-diisopropylphenyl-4,6-diketo-5,5-dimethylpyrimidin-2-ylidene. However, DACs featuring less hindered N-aryl substituents facilitated proton transfer, and the measured PA values were found to be consistent with density functional theory calculations (B3LYP/6-31+G(d)). Notably, the PAs of the DACs studied were similar to those of the NHCs, indicating that the former retain many of the nucleophilic characteristics intrinsic to their parent diaminocarbenes and that the observed differences in chemical reactivity may be primarily attributed to an enhanced electrophilicity.
Co-reporter:Anna Zhachkina Michelson ; Mu Chen ; Kai Wang
Journal of the American Chemical Society 2012 Volume 134(Issue 23) pp:9622-9633
Publication Date(Web):May 2, 2012
DOI:10.1021/ja211960r
3-Methyladenine DNA glycosylase II (AlkA) is an enzyme that cleaves a wide range of damaged bases from DNA. The gas-phase thermochemical properties (tautomerism, acidity, and proton affinity) have been measured and calculated for a series of AlkA purine substrates (7-methyladenine, 7-methylguanine, 3-methyladenine, 3-methylguanine, purine, 6-chloropurine, xanthine) that have not been heretofore examined. The damaged nucleobases are found to be more acidic than the normal nucleobases adenine and guanine. Because of this increased acidity, the damaged bases would be expected to be more easily cleaved from DNA by AlkA (their conjugate bases should be better leaving groups). We find that the gas-phase acidity correlates to the AlkA excision rates, which lends support to an AlkA mechanism wherein the enzyme provides a nonspecific active site, and nucleobase cleavage is dependent on the intrinsic N-glycosidic bond stability.
Co-reporter:Anna Zhachkina Michelson ; Aleksandr Rozenberg ; Yuan Tian ; Xuejun Sun ; Julianne Davis ; Anthony W. Francis ; Valerie L. O’Shea ; Mohan Halasyam ; Amelia H. Manlove ; Sheila S. David
Journal of the American Chemical Society 2012 Volume 134(Issue 48) pp:19839-19850
Publication Date(Web):October 29, 2012
DOI:10.1021/ja309082k
The gas-phase thermochemical properties (tautomeric energies, acidity, and proton affinity) have been measured and calculated for adenine and six adenine analogues that were designed to test features of the catalytic mechanism used by the adenine glycosylase MutY. The gas-phase intrinsic properties are correlated to possible excision mechanisms and MutY excision rates to gain insight into the MutY mechanism. The data support a mechanism involving protonation at N7 and hydrogen bonding to N3 of adenine. We also explored the acid-catalyzed (non-enzymatic) depurination of these substrates, which appears to follow a different mechanism than that employed by MutY, which we elucidate using calculations.
Co-reporter:Anna Zhachkina Michelson, Aaron Petronico, and Jeehiun K. Lee
The Journal of Organic Chemistry 2012 Volume 77(Issue 4) pp:1623-1631
Publication Date(Web):November 23, 2011
DOI:10.1021/jo201991y
The fundamental properties of the parent and substituted 2-pyridones (2-pyridone, 3-chloro-2-pyridone, and 3-formyl-2-pyridone) have been examined in the gas phase using computational and experimental mass spectrometry methods. Newly measured acidities and proton affinities are reported and used to ascertain tautomer preference. These particular substrates (as well as additional 3-substituted pyridones) were chosen in order to examine the correlation between leaving group ability and acidity for moieties that allow resonance delocalization versus those that do not, which is discussed herein.
Co-reporter:Min Liu;Mu Chen;Sisi Zhang;Ill Yang;Brian Buckley
Journal of Physical Organic Chemistry 2011 Volume 24( Issue 10) pp:929-936
Publication Date(Web):
DOI:10.1002/poc.1890
The gas phase reactivity of N-heterocyclic carbenes versus tricyclohexylphosphine (PCy3) is examined computationally and experimentally. New measurements indicate that dimethylimidazol- and 1-ethyl-3-methylimidazol-2-ylidene are more basic than PCy3, in contrast to previous measurements made by us and by others. Proton-bound dimers of the carbenes and PCy3 are also found to exhibit interesting reactivity involving phosphine alkylation, cyclohexene elimination, and/or ethylene elimination. This novel reactivity is further probed and discussed. Copyright © 2011 John Wiley & Sons, Ltd.
Co-reporter:Min Liu, Ngon T. Tran, Annaliese K. Franz, and Jeehiun K. Lee
The Journal of Organic Chemistry 2011 Volume 76(Issue 17) pp:7186-7194
Publication Date(Web):July 19, 2011
DOI:10.1021/jo201214x
The fundamental properties of a series of organic monosilanols, silanediols, disiloxanediols, and known hydrogen-bonding organocatalysts have been examined in the gas phase using computational and experimental mass spectrometry methods. The organosilicon diol molecules contain dual hydrogen-bonding groups that were designed as potential hosts and hydrogen-bonding catalysts. Newly measured acidities are reported, and implications regarding solvent effects, catalysis, and molecular recognition are discussed.
Co-reporter:Min Liu, Ill Yang, Brian Buckley, and Jeehiun K. Lee
Organic Letters 2010 Volume 12(Issue 21) pp:4764-4767
Publication Date(Web):October 1, 2010
DOI:10.1021/ol101864p
The gas-phase proton affinities of unusually basic phosphines and N-heterocyclic carbenes are compared and contrasted both computationally and experimentally.
