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...

This report describes a method for the deoxyfluorination of phenols with sulfuryl fluoride (SOF) and tetramethylammonium fluoride (NMeF) via aryl fluorosulfonate (ArOFs) intermediates. We first demonstrate that the reaction of ArOFs with NMeF proceeds under mild conditions (often at room temperature) to afford a broad range of electronically diverse and functional group-rich aryl fluoride products. This transformation was then translated to a one-pot conversion of phenols to aryl fluorides using the combination of SOF and NMeF. Ab initio calculations suggest that carbon-fluorine bond formation proceeds via a concerted transition state rather than a discrete Meisenheimer intermediate.

This Addendum provides a new set of Python scripts that are compatible with current personal computer operating systems. The scripts provided in the original Protocol 1 (published in 2014) worked on all tested operating systems (Mac, Windows 7, Vista and Linux) at the time of publication, but some of these operating systems have since evolved, leading to potential sorting errors. It is recommended that the Supplementary Data 2.zip, Supplementary Data 3.zip and Supplementary Data 4.zip files provided here be used in place of the three equivalent files associated with the original Protocol.

Phomopsichalasin was isolated and assigned structure 1 over 15 years ago. Analysis of its proton NMR data led us to hypothesize that not all aspects of the relative configuration of this structure were correct. We have used both empirical and computational methods to propose an alternative structure. Diaporthichalasin was reported several years ago, and its structure was assigned as 7, a diastereomer of structure 1, and confirmed by a single crystal X-ray study. We have shown that diaporthichalasin and phomopsichalasin are identical; i.e., both have structure 7. Additional aspects of NMR interpretation that provide guidance for avoiding some of the pitfalls that can lead to incorrect structure assignments are discussed. These recommendations/reminders include i) the use of complementary solvents for acquiring NMR data that break accidental chemical shift degeneracy, ii) the importance of assigning coupling constants as extensively as possible, and iii) exercising caution when interpreting correlations in 2D spectra where overlapping resonances are involved.

The results of several experiments designed to probe the energetic viability of a reaction path for generation of penostatins I (3) and F (4) via spontaneous [3,3]-sigmatropic rearrangement are reported. In particular, the enolate derived from the 2-vinyl-6-acyldihydropyran 8-cis gave cyclooctadienone 12 via facile anionic oxy-Claisen rearrangement, demonstrating the feasibility of such an event.