This protocol details the most commonly used nuclear magnetic resonance (NMR)-based method for deducing the configuration of otherwise unknown stereogenic, secondary carbinol (alcohol) centers (R1R2CHOH (or the analogous amines where OH is replaced by NH2)). This 'Mosher ester analysis' relies on the fact that the protons in diastereomeric alpha-methoxy-alpha-trifluoromethylphenylacetic acid (MTPA) esters (i.e., those derived from conjugation of the carbinol under interrogation with MTPA) display different arrays of chemical shifts (deltas) in their 1H NMR spectra. The protocol consists of the following: (i) preparation of each of the diastereomeric S- and R-MTPA esters and (ii) comparative (Delta delta(SR)) analysis of the 1H NMR spectral data of these two esters. By analyzing the sign of the difference in chemical shifts for a number of analogous pairs of protons (the set of Delta delta(SR) values) in the diastereomeric esters (or amides), the absolute configuration of the original carbinol (or amino) stereocenter can be reliably deduced. A typical Mosher ester analysis requires approximately 4-6 h of active effort over a 1- to 2-d period.
this protocol is intended to provide chemists who discover or make new organic compounds with a valuable tool for validating the structural assignments of those new chemical entities. experimental 1 H and/or 13 c nMr spectral data and its proper interpretation for the compound of interest is required as a starting point. the approach involves the following steps: (i) using molecular mechanics calculations (with, e.g., MacroModel) to generate a library of conformers; (ii) using density functional theory (DFt) calculations (with, e.g., Gaussian 09) to determine optimal geometry, free energies and chemical shifts for each conformer; (iii) determining Boltzmann-weighted proton and carbon chemical shifts; and (iv) comparing the computed chemical shifts for two or more candidate structures with experimental data to determine the best fit. For a typical structure assignment of a small organic molecule (e.g., fewer than ~10 non-H atoms or up to ~180 a.m.u. and ~20 conformers), this protocol can be completed in ~2 h of active effort over a 2-d period; for more complex molecules (e.g., fewer than ~30 non-H atoms or up to ~500 a.m.u. and ~50 conformers), the protocol requires ~3-6 h of active effort over a 2-week period. to demonstrate the method, we have chosen the analysis of the cis-versus the trans-diastereoisomers of 3-methylcyclohexanol (1-cis versus 1-trans). the protocol is written in a manner that makes the computation of chemical shifts tractable for chemists who may otherwise have only rudimentary computational experience. this method certainly has value, the example described next shows that when one moves to the consideration of molecules bearing more than one stereocenter, this approach is no longer adequate.Consider the case of the trans-versus the cis-diastereomers of 3-methylcyclohexanol (1-trans and 1-cis, respectively). The experimental 1 H NMR spectra for 1-trans and 1-cis are shown in Figure 1a,b (see Supplementary Data 1 for a full listing of actual chemical shift values). There are substantial differences in these two spectra, especially within the upfield 0.7-2.1 p.p.m. range. Clearly, it would be valuable if computational approaches could reproduce these sorts of differences sufficiently well to allow confident assignment of structure.Common software packages that use empirical (often increment-based) compilations of chemical shift information (e.g., tabulated shift increments or databases of known spectral data) allow users to predict the chemical shifts of a given input structure. These include 'ChemNMR' within ChemBioDraw (also known as ChemDraw) and 'C+H NMR Predictor and DB' within the ACD/Labs software suite. These methods sometimes can be sufficient for the task of resolving constitutional structural assignments. However, when issues associated with relative configuration are considered, increment-based methods are decidedly ill-equipped. Analysis of structures 1-trans and 1-cis by each of these programs quickly reveals these limitations, even for these simple structures. Namely, because Che...
Summary o-Benzynes (arynes) are among the most versatile of all reactive (short-lived) intermediates in organic chemistry. These species can be trapped to give products that are valuable from the perspective of both fine (pharmaceuticals) and commodity (agrochemicals, dyes, polymers, etc.) chemicals. Here we show a fundamentally new strategy that unites a de novo generation of benzynes, through the title hexadehydro-Diels–Alder (HDDA) reaction, with their in situ elaboration into structurally complex benzenoid products. In the HDDA reaction a 1,3-diyne is engaged in a [4+2] cycloisomerization with a third (pendant) alkyne–the diynophile–to produce the highly reactive benzyne intermediate. The metal- and reagent-free reaction conditions for this simple, thermal transformation are notable. The subsequent and highly efficient trapping reactions increase the power of the overall process. Finally, we provide examples of how this de novo benzyne generation approach allows new modes of intrinsic reactivity to be revealed.
Two hybrid generalized-gradient approximation density functionals, WC04 and WP04, are optimized for the prediction of (13)C and (1)H chemical shifts, respectively, using a training set of 43 molecules in chloroform solution. Tests on molecules not included in the training set, namely six stereoisomeric methylcyclohexanols and a β-lactam antibiotic, indicate the models to be robust and moreover to provide results more accurate than those from equivalent B3LYP, PBE1, or mPW1PW91 calculations, particularly for the prediction of downfield resonances in nuclear magnetic resonance spectra. However, linear regression of the B3LYP, PBE1, and mPW1PW91 predicted values on the experimental data improves the accuracy of those models so that they are comparable to WC04 and WP04.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.