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40920-B4
Computing Through-Space NMR Shielding Effects by Functional Groups of Biochemical Interest and by Small-Ring Hydrocarbons
Our previous work in the area of applying ab initio calculations using GIAO-SCF to predict NMR shielding of protons due to their proximity to certain functional groups provided results that proved to be quite useful in more accurately predicting NMR chemical shifts of organic compounds having the requisite structural features. Two previous ACS-PRF funded projects involved mapping the net computed NMR shielding in the face of the benzene ring, the carbon-carbon double bond, the carbon-carbon triple bond, the carbonyl group, the nitro group, and the nitrile group. Unexpectedly, deshielding was predicted by our calculations for protons over the center of an alkene carbon-carbon double bond. This is in sharp contrast to the shielding predicted due to the magnetic anisotropy according to the long-held “shielding cone model” found in most spectroscopy textbooks. Experimental measurements of chemical shifts in several alkenes confirmed our predictions. This work has also led to a better understanding of the origin of the magnetic shielding effect caused by these groups. These calculations involved use of methane as a probe of through-space NMR shielding effects. In a recent comparison of several possible calculated NMR shielding probes, we have since found that diatomic hydrogen gives comparable results and is considerably simpler to employ.
NMR spectroscopy is widely used in the structure determination of biomolecules, including peptides. In the current research we utilized the same methodology that we have developed and applied successfully in previous work (except for substituting hydrogen in place of the methane probe) to investigate computationally the net magnetic shielding of protons over five common functional groups selected as simple models of much more complex structures found in peptides: the carboxylate ion, the carboxylic acid group, ammonia, the ammonium ion, and the amide group. Of those, only the charged groups cause significant shielding (by cations) or deshielding (by anions). In addition, we have examined NMR shielding over several small-ring hydrocarbons, including some that are aromatic (σ and π) and some that are antiaromatic (σ and π). The sign of the shielding increment at 2.5 Å above the center of a ring is diagnostic of whether the ring is aromatic or antiaromatic. We have also examined the effect of cation-π and π-π complexation on NMR shielding, where a substantial synergistic effect of cation complexation on the shielding effect is noted. Polarization of the bond to the probe atom is responsible for a large proportion of the shielding or deshielding effects in systems other than aromatic rings.
Shielding by aryl-aryl π complexes has been the focus of our investigation this past year. These complexes are important in a number of biochemical applications, such as drug binding, enzyme-substrate complex formation, and others. We have recently reported that such complexes result in through-space NMR shielding effects that are greater than those over each isolated aromatic ring. Furthermore, we have shown that through-space shielding effects of aryl-aryl π complexes offer an explanation of the concentration-dependent NMR spectra often observed in heterocyclic aromatic compounds.
Seven students have been supported by this grant. One of these is pursuing a Ph. D. in chemistry, one is in dental school, two are employed in the chemical/pharmaceutical industry, and three are still undergraduate students. One of these is starting an Honors research project.
The PI spent a semester's leave of absence this past year traveling to meet with authors of NMR textbooks to bring them up to date on through-space NMR shielding research, including this work. Four publications have resulted from this ACS-PRF funded research, and one manuscript is under review.
