Abstract: We report hydroboration of carbodiimide and isocyanate substrates catalyzed by a cyclic carbodiphosphorane catalyst. The cyclic carbodiphosphorane outperformed the other Lewis basic carbon species tested, including other zerovalent carbon compounds, phosphorus ylides, an N-heterocyclic carbene, and an N-heterocyclic olefin. Hydroborations of seven carbodiimides and nine isocyanates were performed at room temperature to form N-boryl formamidine and N-boryl formamide products. Intermolecular competition experiments demonstrated the selective hydroboration of alkyl isocyanates over carbodiimide and ketone substrates. DFT calculations support a proposed mechanism involving activation of pinacolborane by the carbodiphosphorane catalyst, followed by hydride transfer and B–N bond formation.
17. Calcium Bistriflimide-Mediated Sulfur(VI)–Fluoride Exchange (SuFEx): Mechanistic Insights toward Instigating Catalysis
Han, B.; Khasnavis, S. R.; Nwerem, M.; Bertagna, M.; Ball, N. D.;* Ogba, O. M.* Inorg. Chem. 2022, 61 (25), 9746–9755. Link
Abstract: We report a mechanistic investigation of calcium bistriflimide-mediated sulfur(VI)–fluoride exchange (SuFEx) between sulfonyl fluorides and amines. We determine the likely pre-activation resting state─a calcium bistriflimide complex with ligated amines─thus allowing for corroborated calculation of the SuFEx activation barrier at ∼21 kcal/mol, compared to 21.5 ± 0.14 kcal/mol derived via kinetics experiments. Transition state analysis revealed: (1) a two-point calcium-substrate contact that activates the sulfur(VI) center and stabilizes the leaving fluoride and (2) a 1,4-diazabicyclo[2.2.2]octane additive that provides Brønsted-base activation of the nucleophilic amine. Stable Ca–F complexes upon sulfonamide formation are likely contributors to inhibited catalytic turnover, and a proof-of-principle redesign provided evidence that sulfonamide formation is feasible with 10 mol % calcium bistriflimide.
16. 1H NMR Studies of Intramolecular OH/OH Hydrogen Bonds via Titratable Isotope Shifts
Kolahdouzan, K.; Ogba, O. M.; O’Leary, D. J. J. Org. Chem. 2022, 87 (3), 1732–1744. Link
Abstract: Methanol titrations of partially deuterated 1,4- and 1,3-diols dissolved in nonpolar solvents such as CD2Cl2 and benzene-d6 have provided 1H NMR measurements of OH/OD isotope shifts, diagnostic for intact intramolecular hydrogen bonds, under conditions of increasing protic solvent concentration. 1,4- and 1,3-diols with conformationally favored intramolecular OH/OH hydrogen bonds can be titrated to constant isotope shift values, albeit with variable sign, in the presence of excess methanol equivalents, providing evidence for intact intramolecular hydrogen bonds under these conditions. Conversely, the isotope shift in a 1,3-diol with a conformationally labile intramolecular hydrogen bond titrated to zero when in the presence of excess equivalents methanol, consistent with intramolecular hydrogen bond rupture under these conditions. Additionally, the titration behavior of hydroxyl chemical shifts in diols and protected derivatives has revealed significant OH/OD isotope shifts in the absence of chemical shift differences (δOHin = δOHout) that are necessary for an equilibrium isotope effect, lending evidence for an intrinsic contribution to the isotope effect. OH/OD isotope shift titration thus provides a means for understanding the origins of these isotope effects and for probing the intact or nonintact nature of intramolecular OH/OH hydrogen bonds in response to intermolecular hydrogen bonds provided by a protic solvent.
15. A Bacterial Inflammation Sensor Regulates C-Di-GMP Signaling, Adhesion, and Biofilm Formation
Perkins, A.; Tudorica, D. A.; Teixeira, R. D.; Schirmer, T.; Zumwalt, L.; Ogba, O. M.; Cassidy, C. K.; Stansfeld, P. J.; Guillemin, K. A. Mbio 2021, 12 (3), e00173-21. Link.
Abstract: Bacteria that colonize animals must overcome, or coexist, with the reactive oxygen species products of inflammation, a front-line defense of innate immunity. Among these is the neutrophilic oxidant bleach, hypochlorous acid (HOCl), a potent antimicrobial that plays a primary role in killing bacteria through nonspecific oxidation of proteins, lipids, and DNA. Here, we report that in response to increasing HOCl levels, Escherichia coli regulates biofilm production via activation of the diguanylate cyclase DgcZ. We identify the mechanism of DgcZ sensing of HOCl to be direct oxidation of its regulatory chemoreceptor zinc-binding (CZB) domain. Dissection of CZB signal transduction reveals that oxidation of the conserved zinc-binding cysteine controls CZB Zn2+ occupancy, which in turn regulates the catalysis of c-di-GMP by the associated GGDEF domain. We find DgcZ-dependent biofilm formation and HOCl sensing to be regulated in vivo by the conserved zinc-coordinating cysteine. Additionally, point mutants that mimic oxidized CZB states increase total biofilm. A survey of bacterial genomes reveals that many pathogenic bacteria that manipulate host inflammation as part of their colonization strategy possess CZB-regulated diguanylate cyclases and chemoreceptors. Our findings suggest that CZB domains are zinc-sensitive regulators that allow host-associated bacteria to perceive host inflammation through reactivity with HOCl.
14. Mechanism and Chemoselectivity for HOCl‐Mediated Oxidation of Zinc‐Bound Thiolates
Zumwalt, L.; Perkins, A.; Ogba, O. M.* ChemPhysChem 2020, 21 (21), 2384–2387. Link.
Abstract: Quantum mechanical calculations reveal the preferred mechanism and origins of chemoselectivity for HOCl-mediated oxidation of zinc-bound thiolates implicated in bacterial redox sensing. Distortion/interaction models show that minimizing geometric distortion at the zinc complex during the rate-limiting nucleophilic substitution step controls the mechanistic preference for OH over Cl transfer with HOCl and the chemoselectivity for HOCl over H2O2.
13. Midsemester Transition to Remote Instruction in a Flipped College-Level Organic Chemistry Course
Liberman-Martin, A. L.; Ogba, O. M. Midsemester Transition to Remote Instruction in a Flipped College-Level Organic Chemistry Course. J. Chem. Educ. 2020, 97 (9), 3188–3193. Link.
Abstract: This report describes rapid changes to instructional materials, assessment, and technology use in a flipped college-level organic chemistry course in response to the sudden COVID-19 campus closures and midsemester transition to remote learning. The instructors modified in-class instructional materials to accommodate students’ preference for text-based over audiovisual engagement in the remote environment. The pros and cons of three approaches to administering remote organic chemistry exams are presented. Issues related to equitable incorporation of technology and maintaining academic integrity are discussed.
12. Vibrational analysis of a rate-slowing conformational kinetic isotope effect
Ogba, O.; Liu, Z.; O’Leary, D. J. Vibrational Analysis of a Rate-Slowing Conformational Kinetic Isotope Effect. Tetrahedron 2019, 75 (5), 545–550. https://doi.org/10.1016/j.tet.2018.12.051.
Abstract: An enthalpy-entropy approach to analyzing a rate-slowing conformational kinetic isotope effect (CKIE) in a deuterated doubly-bridged biaryl system is described. The computed isotope effect (kH/kD = 1.075, 368 K) agrees well with the measured value (kH/kD = 1.06, 368 K). The rate-slowing (normal isotope effect) nature of the computed CKIE is shown to originate from a vibrational entropy contribution defined by the twenty lowest frequency normal modes in the ground state and transition state structures. This normal entropy contribution is offset by an inverse vibrational enthalpy contribution, which also arises from the twenty lowest frequency normal modes. Zero point vibrational energy contributions are found to be relatively small when all normal modes are considered. Analysis of the HZPE, Hvib, and Svib energy terms arising from the low frequency vibrational modes reveals their signs and magnitudes are determined by larger vibrational energy differences in the labeled and unlabeled ground state structures.
11. Evaluating Computational and Structural Approaches to Predict Transformation Products of Polycyclic Aromatic Hydrocarbons
Titaley, I. A.; Walden, D. M.; Dorn, S. E.; Ogba, O. M.; Massey Simonich, S. L.; Cheong, P. H.-Y. Evaluating Computational and Structural Approaches to Predict Transformation Products of Polycyclic Aromatic Hydrocarbons. Environ. Sci. Technol. 2019, 53 (3), 1595–1607. https://doi.org/10.1021/acs.est.8b05198.
Abstract: Polycyclic aromatic hydrocarbons (PAHs) undergo transformation reactions with atmospheric photochemical oxidants, such as hydroxyl radicals (OH•), nitrogen oxides (NOx), and ozone (O3). The most common PAH-transformation products (PAH-TPs) are nitrated, oxygenated, and hydroxylated PAHs (NPAHs, OPAHs, and OHPAHs, respectively), some of which are known to pose potential human health concerns. We sampled four theoretical approaches for predicting the location of reactive sites on PAHs (i.e., the carbon where atmospheric oxidants attack), and hence the chemoselectivity of the PAHs. All computed results are based on density functional theory (B3LYP/6-31G(d) optimized structures and energies). The four approaches are (1) Clar’s prediction of aromatic resonance structures, (2) thermodynamic stability of all OHPAH adduct intermediates, (3) computed atomic charges (Natural Bond order, ChelpG, and Mulliken) at each carbon on the PAH, and (4) average local ionization energy (ALIE) at atom or bond sites. To evaluate the accuracy of these approaches, the predicted PAH-TPs were compared to published laboratory observations of major NPAH, OPAH, and OHPAH products in both gas and particle phases. We found that the Clar’s resonance structures were able to predict the least stable rings on the PAHs but did not offer insights in terms of which individual carbon is most reactive. The OHPAH adduct thermodynamics and the ALIE approaches were the most accurate when compared to laboratory data, showing great potential for predicting the formation of previously unstudied PAH-TPs that are likely to form in the atmosphere.
10. 1H and 13C NMR assignments for (N‐Methyl)‐(−)‐(α)‐isosparteinium iodide and (N‐Methyl)‐(−)‐sparteinium iodide,
Kolahdouzan, K.; Ogba, O. M.; O’Leary, D. J. 1H and 13C NMR Assignments for (N‐Methyl)‐(−)‐(α)‐isosparteinium Iodide and (N‐Methyl)‐(−)‐sparteinium Iodide. Magn Reson Chem 2019, 57 (1), 55–64. https://doi.org/10.1002/mrc.4792.
9. Recent advances in ruthenium-based olefin metathesis
Ogba, O. M.; Warner, N. C.; O’Leary, D. J.; Grubbs, R. H. Recent Advances in Ruthenium-Based Olefin Metathesis. Chem. Soc. Rev. 2018, 47 (12), 4510–4544. https://doi.org/10.1039/C8CS00027A.
Abstract: Ruthenium-based olefin metathesis catalysts, known for their functional group tolerance and broad applicability in organic synthesis and polymer science, continue to evolve as an enabling technology in these areas. A discussion of recent mechanistic investigations is followed by an overview of selected applications.
8. Automating data analysis for two-dimensional gas chromatography/time-of-flight mass spectrometry non‐targeted analysis of comparative samples
Titaley, I. A.; Ogba, O. M.; Chibwe, L.; Hoh, E.; Cheong, P. H.-Y.; Simonich, S. L. M. Automating Data Analysis for Two-Dimensional Gas Chromatography/Time-of-Flight Mass Spectrometry Non‐targeted Analysis of Comparative Samples. Journal of Chromatography A 2018, 1541, 57–62. https://doi.org/10.1016/j.chroma.2018.02.016.
Abstract: Non-targeted analysis of environmental samples, using comprehensive two‐dimensional gas chromatography coupled with time-of-flight mass spectrometry(GC × GC/ToF-MS), poses significant data analysis challenges due to the large number of possible analytes. Non-targeted data analysis of complex mixtures is prone to human bias and is laborious, particularly for comparative environmental samples such as contaminated soil pre- and post-bioremediation. To address this research bottleneck, we developed OCTpy, a Python™ script that acts as a data reduction filter to automate GC × GC/ToF-MS data analysis from LECO®ChromaTOF® software and facilitates selection of analytes of interest based on peak area comparison between comparative samples. We used data from polycyclic aromatic hydrocarbon (PAH) contaminated soil, pre- and post‐bioremediation, to assess the effectiveness of OCTpy in facilitating the selection of analytes that have formed or degraded following treatment. Using datasets from the soil extracts pre- and post‐bioremediation, OCTpy selected, on average, 18% of the initial suggested analytes generated by the LECO® ChromaTOF® software Statistical Compare feature. Based on this list, 63–100% of the candidate analytes identified by a highly trained individual were also selected by OCTpy. This process was accomplished in several minutes per sample, whereas manual data analysis took several hours per sample. OCTpy automates the analysis of complex mixtures of comparative samples, reduces the potential for human error during heavy data handling and decreases data analysis time by at least tenfold.
7. Origins of Small Proton Chemical Shift Differences in Monodeuterated Methyl Groups
Ogba, O. M.; Elliott, S. J.; Kolin, D. A.; Brown, L. J.; Cevallos, S.; Sawyer, S.; Levitt, M. H.; O’Leary, D. J. Origins of Small Proton Chemical Shift Differences in Monodeuterated Methyl Groups. J. Org. Chem. 2017, 82(17), 8943–8949. https://doi.org/10.1021/acs.joc.7b01356.
Abstract: We have recently shown that the small proton chemical shift difference in 2-methyl-1-(methyl-d)piperidine supports a long-lived nuclear spin state. To identify additional candidate molecules with CH2D groups exhibiting accessible long-lived states, and to investigate the factors governing the magnitude of the shift differences, we report a computational and experimental investigation of methyl rotational equilibria and proton chemical shifts in a variety of 2-substituted 1-(methyl-d)piperidines. The polarity and size of the 2-substituent affect the 1,2-stereoisomeric relationship, and consequently, the strength of the rotational asymmetry within the CH2D group. Nonpolar and large 2-substituents prefer the equatorial position, and relatively large shift differences (i.e., > 13 ppb) are observed. Polar and small substituents, however, increasingly prefer the axial position, and medium to small shift differences (i.e., 0 to 9 ppb) are observed. In addition, the diastereotopic CH2D proton chemical shift difference for tricarbonyl(1-chloro-2-deuteriomethylbenzene) chromium(0) was computed, showing that reasonable predictions of these small shift differences can be extended to more complex, organometallic species.
6. Spreadsheet-Based Computational Predictions of Isotope Effects
Ogba, O. M.; Thoburn, J. D.; O’Leary, D. J. Spreadsheet-Based Computational Predictions of Isotope Effects, Chapter 14 in Applied Theoretical Organic Chemistry (Editor: Tantillo, D. J). 2017, 403–450. https://doi.org/10.1142/9781786344090_0014.
5. Conformational Searching for Complex, Flexible Molecules
Brueckner, A. C.; Ogba, O. M.; Snyder, K. M.; Richardson, H. C.; Cheong, P. H.-Y. Conformational Searching for Complex, Flexible Molecules, Chapter 5 in Applied Theoretical Organic Chemistry (Editor: Tantillo, D. J). 2017, 147–164. https://doi.org/10.1142/9781786344090_0005.
4. MIDA boronates are hydrolysed fast and slow by two different mechanisms
Gonzalez, J. A.; Ogba, O. M.; Morehouse, G. F.; Rosson, N.; Houk, K. N.; Leach, A. G.; Cheong, P. H.-Y.; Burke, M. D.; Lloyd-Jones, G. C. MIDA Boronates Are Hydrolysed Fast and Slow by Two Different Mechanisms. Nat Chem 2016, 8 (11), 1067–1075. https://doi.org/10.1038/nchem.2571.
Abstract: MIDA boronates (N-methylimidodiacetic boronic acid esters) serve as an increasingly general platform for small-molecule construction based on building blocks, largely because of the dramatic and general rate differences with which they are hydrolysed under various basic conditions. Yet the mechanistic underpinnings of these rate differences have remained unclear, which has hindered efforts to address the current limitations of this chemistry. Here we show that there are two distinct mechanisms for this hydrolysis: one is base mediated and the other neutral. The former can proceed more than three orders of magnitude faster than the latter, and involves a rate-limiting attack by a hydroxide at a MIDA carbonyl carbon. The alternative ‘neutral’ hydrolysis does not require an exogenous acid or base and involves rate-limiting B–N bond cleavage by a small water cluster, (H2O)n. The two mechanisms can operate in parallel, and their relative rates are readily quantified by 18O incorporation. Whether hydrolysis is ‘fast’ or ‘slow’ is dictated by the pH, the water activity and the mass-transfer rates between phases. These findings stand to enable, in a rational way, an even more effective and widespread utilization of MIDA boronates in synthesis.
3. Peroxiredoxin Catalysis at Atomic Resolution
Perkins, A.; Parsonage, D.; Nelson, K. J.; Ogba, O. M.; Cheong, P. H.-Y.; Poole, L. B.; Karplus, P. A. Peroxiredoxin Catalysis at Atomic Resolution. Structure 2016, 24 (10), 1668–1678. https://doi.org/10.1016/j.str.2016.07.012.
Summary: Peroxiredoxins (Prxs) are ubiquitous cysteine-based peroxidases that guard cells against oxidative damage, are virulence factors for pathogens, and are involved in eukaryotic redox regulatory pathways. We have analyzed catalytically active crystals to cap- ture atomic resolution snapshots of a PrxQ subfamily enzyme (from Xanthomonas campestris) proceeding through thiolate, sulfenate, and sulfinate species. These analyses provide structures of unprecedented accuracy for seeding theoretical studies, and reveal conformational intermediates giving insight into the reaction pathway. Based on a highly non-standard geometry seen for the sulfenate intermediate, we infer that the sulfenate formation itself can strongly promote local unfolding of the active site to enhance productive catalysis. Further, these structures reveal that preventing local unfolding, in this case via crystal contacts, results in facile hyperoxidative inactivation even for Prxs normally resistant to such inactivation. This supports previous proposals that conformation specific inhibitors may be useful for achieving selective inhibition of Prxs that are drug targets.
2. Computational Insights into the Central Role of Nonbonding Interactions in Modern Organocatalysis
Walden, D. M.; Ogba, O. M.; Johnston, R. C.; Cheong, P. H.-Y. Computational Insights into the Central Role of Nonbonding Interactions in Modern Covalent Organocatalysis. Accounts Chem Res 2016, 49 (6), 1279–1291. https://doi.org/10.1021/acs.accounts.6b00204.
1. Letter Writing as a Service-Learning Project: An Alternative to the Traditional Laboratory Report
Burand, M. W.; Ogba, O. M. Letter Writing as a Service-Learning Project: An Alternative to the Traditional Laboratory Report. J Chem Educ 2013, 90 (12), 1701–1702. https://doi.org/10.1021/ed400215p.