Research Synopsis: Biophysical organic and analytical chemistry, computational chemistry, mass spectrometry, study of chemical reactivity, recognition, and catalysis
Our group combines experimental and computational methods to understand mechanisms of reactions important for chemistry and biology. Specifically, we utilize traditionally physical methods, primarily mass spectrometry and computational chemistry, to tackle problems at the chemistry/biology interface, focusing on catalysis. We work on both biological catalysis, uncovering the mechanisms by which enzymes excise damaged DNA from the genome; as well as organic catalysis, examining N-heterocyclic carbenes as organocatalysts.
Organic catalysis. N-Heterocyclic carbenes (NHCs) are organic species that have a wide variety of applications, including as effective ligands for transition-metal-catalyzed reactions; as catalysts in their own right, for a range of organic transformations; and in protonated form, as environmentally "clean" (green) nonvolatile solvents for organic reactions (ionic liquids). Despite the widespread use of NHCs, their fundamental reactivity is not fully characterized. Our group has developed novel mass spectrometric methodology to measure the thermochemical properties and explore the reactivity of such carbenes. Recent work has provided the first experimental evidence for the high nucleophilicity of a series of diamidocarbenes, which are newly designed NHCs that display both nucleophilic and electrophilic properties (in collaboration with Professor Christopher Bielawski, UT Austin). We are also working on elucidating the mechanism of the Stetter reaction, a highly useful synthetic transformation catalyzed by NHCs. This work will contribute to the design and understanding of new carbene scaffolds and the development of new catalysts for organic transformations.
Biological catalysis. DNA reactivity and stability are critical issues for all living beings. The heterocyclic bases of nucleic acids are targets for toxins that damage DNA, events that are linked to carcinogenesis and cell death. A family of enzymes called DNA glycosylases protect the human genome from the lethal effects of mutated DNA by the base excision repair pathway. We have developed a hypothesis to explain how certain glycosylases differentiate normal from damaged bases. Various lines of evidence have led to the conclusion that glycosylases achieve selectivity by providing a hydrophobic environment that helps differentiate normal from damaged DNA bases. The gas phase is the "ultimate" hydrophobic environment, and our studies of reactions by calculations and novel mass spectrometry methods reveal intrinsic reactivity that is relevant to biological hydrophobic environments such as enzyme active sites. The group is also embarking on enzyme kinetics studies to test hypotheses regarding glycosylase mechanisms. Given the cytotoxic and mutagenic effects of DNA damage, this work has broad implications for aging and for diseases including cancer.
Wang, N.; Lee, J. K. "Gas-Phase and Ionic Liquid Experimental and Computational Studies of Imidazole Acidity and Carbon Dioxide Capture," J. Org. Chem., 2019, https://doi.org/10.1021/acs.joc.9b02193.
Lee, J. K. "Gas Phase Models for Biocatalysis," in "Gas Phase Models for Catalysis: Atoms, Molecules, Clusters, and Complexes/Physical Chemistry in Action," Lang, S.; Berhardt, T.. Eds. Springer, 2019, in press.
Xu, J.; Krajewski, A. E.; Niu, Y.; Kiruba, G. S. M.; Lee, J. K. "Kinetic Hydricity of Silane Hydrides in the Gas Phase," Chemical Science, 2019, DOI:10.1039/C9SC02118C.
Xu, J.; Mieres-Perez, J.; Sanchez-Garcia, E.; Lee, J.K. "Gas-Phase Deprotonation of Benzhydryl Cations: Carbene Basicity, Multiplicity, and Rearrangements," J. Org. Chem., 2019, 84, 7685-7693. Also highlighted as journal issue cover.
Wang, N.; Xu, J.; Lee, J. K. “The Importance of N-Heterocyclic Carbene Basicity in Organocatalysis,” Org. Biomol. Chem., 2018, 16, 6852-6866.
Lee, J. K.; Niu, Y. "pKa Prediction," in "Applied Theoretical Organic Chemistry," World Scientific, 2018, 503-518.
Niu, Y.; Wang, N.; Munoz, A.; Xu, J.; Zeng, H.; Rovis. T.; Lee, J. K. "Experimental and Computational Gas Phase Acidities of Conjugate Acids of Triazolylidene Carbenes: Rationalizing Subtle Electronic Effects," J. Am. Chem. Soc., 2017, 139, 14917-14930.
Bird, J. G.; Zhang, Y.; Tian, Y.; Greene, L.; Liu, M.; Buckley, B.; Lee, J. K.; Kaplan, C. D.; Ebright, R. H.; Nickels, B. E. "The Mechanism of RNA 5' Capping with NAD+, NADH, and CoA," Nature, 2016, 535, 444-447.
Kiruba, G. S. M.; Xu, J.; Zelikson, V.; Lee, J. K. "Gas Phase Studies of Formamidopyrimidine Glycosylase (Fpg) Substrates," Chem. Eur. J., 2016, 22, 3881-3890 (special issue "Women in Chemistry")
Tian, Y.; Lee, J. K. "Gas Phase Studies of N-Heterocyclic Carbene-Catalyzed Condensation Reactions," J. Org. Chem., 2015, 80, 6831-6838. Selected by "Organic Process Research & Development" as a "Highlight from the Literature"
Teator, A. J.; Tian, Y.; Chen, M.; Lee, J. K.; Bielawski, C. W. "An Isolable, Photoswitchable N-Heterocyclic Carbene: On-Demand Reversible Ammonia Activation," Angew. Chemie Int. Ed., 2015, 54, 11559-11563.
Chen, M.; Lee, J. K. "Computational Studies of the Gas-Phase Thermochemical Properties of Modified Nucleobases," J. Org. Chem., 2014, 79, 11295-1130. Selected as "Highlighted Article"
Zeng, H.; Wang, K.; Tian, Y.; Niu, Y.; Greene, L.; Hu, Z.; Lee, J. K. "The Benzoin Condensation: Charge Tagging of the Catalyst Allows for Tracking by Mass Spectrometry," Int. J. Mass. Spectrom., 2014, 369, 92-97.
Wang, K.; Chen, M.; Wang, Q.; Shi, X.; Lee, J. K. "1,2,3-Triazoles: Gas Phase Properties," J. Org. Chem., 2013, 78, 7249-7258.
Chen, M.; Moerdyk, J. P.; Blake, G. A.; Bielawski, C. W.; Lee, J. K. "Assessing the Proton Affinities of N,N'-Diamidocarbenes," J. Org. Chem., 2013, 78, 10452–10458 ("Highlighted Article")
Maiti, A.; Michelson, A. Z.; Hwang, B.-J.; Armwood, C. J.; Lu, A.-L.; Lee, J. K.; Drohat, A. C. "Divergent Mechanisms for TDG Excision of 5-Formylcytosine and 5-Carboxylcytosine from DNA," J. Am. Chem. Soc., 2013, 135, 15813-15822.
Michelson, A. Z.; Rozenberg, A.; Tian, Y.; Sun, X.; Davis, J.; Francis, A. W.; O'Shea, V. L.; Halasyam, M.: Manlove, A. H.; David, S. S.; Lee, J. K. "Gas-Phase Studies of Substrates for the DNA Mismatch Repair Enzyme MutY," J. Am. Chem. Soc., 2012, 134, 19839-19850.
Michelson, A. Z.; Chen, M.; Wang, K.; Lee, J. K. "Gas-Phase Studies of Purine 3-Methyladenine DNA Glycosylase II (AlkA) Substrates," J. Am. Chem. Soc., 2012, 134, 9622-9633.
Michelson, A. Z.; Petronico, A.; Lee, J. K. "2-Pyridone and Derivatives: Gas Phase Acidity, Proton Affinity, Tautomer Preference and Leaving Group Ability," J. Org. Chem., 2012, 77, 1623-1631.
Liu, M.; Chen, M.; Zhang, S.; Yang, I.; Buckley, B.; Lee, J. K. "Reactivity of Carbene•Phosphine Dimers: Proton Affinity Revisited," J. Phys. Org. Chem. 2011, 24, 929-936.
Lee, J. K.; Tantillo, D. J. "Reaction Mechanisms: Pericyclic Reactions," Annu. Rep. Prog. Chem., Sect. B 2011, 107, 266-286.
Liu, M.; Tran, N. T.; Franz, A. K.; Lee, J. K. "Gas-Phase Acidity Studies of Dual Hydrogen-Bonding Organic Silanols and Organocatalysts," J. Org. Chem. 2011, 76, 7186-7194.
Liu, M.; Yang, I.; Buckley, B.; Lee, J. K. "Proton Affinities of Phosphines versus N-Heterocyclic Carbenes," Org. Lett. 2010, 21, pp 4764–4767.
Lee, J. K.; Tantillo, D. J. "Reaction Mechanisms: Pericyclic Reactions," Annu. Rep. Prog. Chem., Sect. B 2010, 106, 283-303.
Sun, X.; Lee, J. K. "The Stability of DNA Duplexes Containing Hypoxanthine (Inosine): Gas versus Solution Phase and Biological Implications," J. Org. Chem., 2010, 75, 1848-1854.
Zhachkina, A.; Lee, J. K. "Uracil and Thymine Reactivity in the Gas Phase: The SN2 Reaction and Implications for Electron Delocalization in Leaving Groups," J. Am. Chem. Soc. 2009, 131, 18376-18385.
Zhachkina, A.; Liu, M.; Sun, X.; Amegayibor, F. S.; Lee, J. K. "Gas-Phase Thermochemical Properties of the Damaged Base O-Methylguanine versus Adenine and Guanine," J. Org. Chem. 2009, 74, 7429-7440.
Tantillo, D. J.; Lee, J. K. "Reaction Mechanisms: Pericyclic Reactions," Annu. Rep. Prog. Chem., Sect. B, 2009, 105, 285-309.
Liu, M; Li, T.; Amegayibor, F. S.; Cardoso, D. S.; Fu, Y.; Lee, J. K. “Gas-Phase Thermochemical Properties of Pyrimidine Nucleobases,” J. Org. Chem. 2008, 73, 9283-9291.
Rozenberg, A; Lee, J. K. “Theoretical Studies of the Quinolinic Acid to Nicotinic Acid Mononucleotide Transformation,” J. Org. Chem. 2008, 73, 9314-9319.
Wepukhulu, W. O.; Smiley, V. L.; Vemulapalli, B.; Smiley, J. A.; Phillips, L. M.; Lee, J. K. “Evidence for Pre-Protonation in the Catalytic Reaction of OMP Decarboxylase: Kinetic Isotope Effects using the Remote Double Label Method,” Organic and Biomolecular Chemistry 2008, 6, 4533-4541 (ALSO FEATURED ON COVER).
Tantillo, D. J.; Lee, J. K. “Reaction Mechanisms: Pericyclic Reactions,” Annu. Rep. Prog. Chem., Sect. B. 2008, 104, 260-283.
Liu, M.; Xu, M.; Lee, J. K. “The Intrinsic Reactivity of Ethenoadenine and Mechanism for Excision from DNA,” J. Org. Chem. 2008, 73, 5907-5914.
Sun, X.; Lee, J. K. “The Acidity and Proton Affinity of Hypoxanthine in the Gas Phase versus in Solution: Intrinsic Reactivity and Biological Implications,” J. Org. Chem. 2007, 72, 6548-6555.
Tantillo, D. J.; Lee, J. K. “Reaction Mechanisms: Pericyclic Reactions,” Annu. Rep. Prog. Chem., Sect. B. 2007, 103, 272-293.
Pan, S.; Sun, X.; Lee, J. K. “DNA Stability in the Gas versus Solution Phases: A Systematic Study of Thirty-One Duplexes with Varying Length, Sequence, and Charge Level,” J. Am. Soc. Mass Spectrom. 2006, 17, 1383-1395.
Pan, S.; Sun, X.; Lee, J. K. “Stability of Complementary and Mismatched DNA Duplexes: Comparison and Contrast in Gas versus Solution Phases,” Int. J. Mass Spectrom. 2006, 253, 238-248.
Pan, S.; Verhoeven, K.; Lee, J. K. “Investigation of the Initial Fragmentation of Oligodeoxynucleotides in a Quadrupole Ion Trap: Charge Level-Related Base Loss,” J. Am. Soc. Mass Spectrom. 2005, 16, 1863-1865.
Phillips, L. M; Lee, J. K. “Theoretical Studies of the Effect of Thio Substitution on Orotidine Monophosphate Decarboxylase Substrates,” J. Org. Chem. 2005, 70, 1211-1221.
Lee, J. K. “Insights into Nucleic Acid Reactivity through Gas Phase Studies,” Int. J. Mass Spectrom. 2005, 240, 261-272.
Sharma, S.; Lee, J. K. “Gas Phase Acidity Studies of Multiple Sites of Adenine and Adenine Derivatives,” J. Org. Chem. 2004, 69, 7018-7025.
Lee, J. K., Editor. “Orotidine Monophosphate Decarboxylase: A Mechanistic Dialogue,” Topics in Current Chemistry 2004.
Lee, J. K.; Tantillo, D. J. “Computational Studies on the Mechanism of Action of Orotidine Monophosphate Decarboxylase,” Adv. Phys. Org. Chem. 2003, 38, 183-218.
Haeffner, F.; Houk, K. N.; Schulze, S. M.; Lee, J. K. “Concerted Rearrangement versus Heterolytic Cleavage in Anionic [2,3]- and [3,3]-Sigmatropic Shifts. A DFT Study of Relationships Between Anion Stabilities and Mechanisms and Rates,” J. Org. Chem. 2003, 68 2310-2316.
Kurinovich, M. A.; Phillips, L. M.; Sharma, S.; Lee, J. K. “The Gas Phase Proton Affinity of Uracil: Measuring Multiple Basic Sites and Implications for the Enzyme Mechanism of Orotidine 5-Monophosphate Decarboxylase,” Chem. Commun. 2002, 2354-2355.
Sharma, S.; Lee, J. K. “The Acidity of Adenine and Adenine Derivatives and Biological Implications. A Computational and Experimental Gas Phase Study,” J. Org. Chem. 2002, 67, 8360-8365.
Kurinovich, M. A.; Lee, J. K. “The Acidity of Uracil and Uracil Analogs in the Gas Phase: Four Surprisingly Acidic Sites and Biological Implications” J. Am. Soc. Mass. Spectrom. 2002, 13, 985-995.
Phillips, L. M.; Lee, J. K. “Theoretical Studies of Mechanisms and Kinetic Isotope Effects on the Decarboxylation of Orotic Acid and Derivatives,” J. Am. Chem. Soc. 2001, 123, 12067-12073.
Schulze, S. M.; Santella, N.; Grabowski, J. J., Lee, J. K. “The Secondary and Tertiary Anionic Oxy-Cope Alkoxides Rearrange in the Gas Phase,” J. Org. Chem. 2001, 66, 7247-7253.
Houk, K. N.; Lee, J. K.; Tantillo, D. J.; Bahmanyar, S.; Hietbrink, B. N. “Crystal Structures of Orotidine Monophosphate Decarboxylase: Does the Structure Reveal the Mechanism of Natures Most Proficient Enzyme?,” ChemBioChem 2001, 2, 113-118.
Kurinovich, M.A.; Lee, J, K. “The Acidity of Uracil from the Gas Phase to Solution: The Coalescence of the N1 and N3 Sites and Implications for Biological Glycosylation,” J. Am. Chem. Soc. 2000,122, 6258-6262.
Singleton, D. A.; Merrigan, S. R.; Kim, B. J.; Beak, P.; Phillips, L. M.; Lee, J. K. “13C Kinetic Isotope Effects and the Mechanism of the Uncatalyzed Decarboxylation of Orotic Acid,” J. Am. Chem. Soc. 2000, 122, 3296-3300.
Chen, J.; McAllister, M. A., Lee, J. K., Houk, K. N. “Short, Strong Hydrogen Bonds in the Gas Phase and in Solution: Theoretical Exploration of pKa Matching and Environmental Effects on the Strengths of Hydrogen Bonds, and their Potential Roles in Enzymatic Catalysis,” J. Org. Chem. 1998, 63, 4611-4619.
Yoo, H. Y.; Houk, K. N.; Lee, J. K.; Scialdone, M. A.; Meyers, A. I. “A New Paradigm for Anionic Heteroatom Cope Rearrangements,” J. Am. Chem. Soc. 1998, 120, 205-206.
Lee, J. K.; Houk, K. N. “A Proficient Enzyme Revisited: The Predicted Mechanism for Orotidine Monophosphate Decarboxylase,” Science 1997, 276, 942-945. Reported in “News of the Week“: Rouhi, A. M. “Carbenes May Be Key to Enzymes Power,” Chemical and Engineering News 1997, 75, 12.
Lee, J. K.; Houk, K. N. “Cation Cyclization Selectivity: Variable Structures of Protonated Cyclopropanes and Selectivity Control by Catalytic Antibodies,” Angew. Chem. Int. Ed. Engl. 1997, 36, 1003-1005.
Houk, K. N.; Lee, J. K. “Physical Organic in the 21st Century: Evanescent or Transcendent?,” Pure Appl. Chem. 1997, 69, 237-239.
Houk, K. N.; Beno, B. R.; Nendel, M.; Black, K.; Yoo, H. Y.; Wilsey, S.; Lee, J. K. “Exploration of Pericyclic Reaction Transition Structures with Quantum Mechanical Methods: Competing Concerted and Stepwise Mechanisms,” J. Mol. Struct. (Theochem.) 1997, 398-399, 169-179.
Lee, J. K.; Grabowski, J. J. “Anion Structure Determination in the Gas Phase: Chemical Reactivity as a Probe,” J. Org. Chem. 1996, 61, 9422-9429.
Wu, Y.-D.; Lee, J. K.; Houk, K. N.; Dondoni, A. “Theoretical Study of a Termolecular Mechanism for the Reaction of (Trimethyl)silylthiazole with Carbonyl Compounds,” J. Org. Chem. 1996, 61, 1922-1926.