NMR and DFT investigations of structure of colchicine in various solvents including density functional theory calculations

Abstract

A detailed NMR investigation of the chemical shifts of hydrogen and carbon atoms associated with the structure of the naturally occurring alkaloid colchicine was conducted using high field NMR. Initially, the experimental chemical shifts for colchicine in chloroform and DMSO were compared to the values calculated using density functional theory (DFT). There were significant deviations observed for the chloroform solvent, but these were only slight in the DMSO solution. Dilution of the chloroform solution changed the experimental chemical shifts and improved agreement with the DFT calculations, suggesting self-aggregation at higher concentrations. A dimeric model was proposed for which agreement with the DFT calculated chemical shifts was better than for corresponding monomeric structures. Three further solvents were studied to evaluate changes in chemical shift values at different dilutions. Chloroform, benzene and water showed significant chemical shift changes implying self-aggregation, whereas DMSO and acetone did not show significant change upon dilution.

Questioning the γ-gauche effect: stereoassignment of 1,3-disubstituted-tetrahydro-β-carbolines using1H–1H coupling constants

“…A recent study of the calculated 13 C NMR spectrum of colchicine in CDCl 3 also noted improved accuracy of the mPW1PW91 functional relative to B3LYP, and our calculated MAD (1.4 ppm) is even lower than they reported (1.9 ppm). 49 As can be seen in Table 7, 13 C NMR chemical shifts for C3, C1, C=O, and C1' calculated by this method very closely match the observed values (italics) for all four compounds, with deviations generally less than 2 ppm. Looking at the difference in chemical shift for a particular carbon between diastereomers (Δδ 7-8 ), the congruity is even better.…”

“…As described below, the 6-311+G(2d,p) basis set, mPW1PW91 functional, and PCM solvation model were chosen based on their suitability for 13 C NMR shift calculations. 49 In addition, we also calculated single point energies at M06-2X/def2-TZVP (with PCM solvation), since the M06-2X functional 50,51 has been recommended for accurate energies of conformers, especially in conjunction with the def2-TZVP basis set. 52,53 Free energy corrections (based on B3LYP/6-31G(d) frequencies) were then applied to these single point energies (Tables S6-S13).…”

“…These functionals, basis set, and solvation model were selected based on their excellent performance in a recent study of colchicine. 49 The weighted average 13 C NMR chemical shifts of each carbon in 7a, 7b, 8a, and 8b were then calculated using the calculated Boltzmann populations; mean average deviations (MAD) of the calculated chemical shifts from the observed values were calculated to assess the performance of each functional. As seen in Table 6, both functionals predict 13 C NMR chemical shifts well, giving MAD of ~2 ppm or less.…”

“…These functionals, basis set, and solvation model were selected based on their excellent performance in a recent study of the 1 H and 13 C NMR solution spectra of colchicine. 49 The corresponding 13 C NMR chemical shifts were calculated according to the formula δ = (σ -b)/a, where a = slope and b = intercept. 59 The values of a and b were taken from the aforementioned study of colchicine, 49 and were a = −1.043 , b = 181.717 for B3LYP/6-311+G(2d,p) (PCM=CHCl 3 ), and a = −1.042, b = 186.357 for mPW1PW91/6-311+G(2d,p) (PCM=CHCl 3 ).…”

“…49 The corresponding 13 C NMR chemical shifts were calculated according to the formula δ = (σ -b)/a, where a = slope and b = intercept. 59 The values of a and b were taken from the aforementioned study of colchicine, 49 and were a = −1.043 , b = 181.717 for B3LYP/6-311+G(2d,p) (PCM=CHCl 3 ), and a = −1.042, b = 186.357 for mPW1PW91/6-311+G(2d,p) (PCM=CHCl 3 ). The weighted average 13 C chemical shifts of each carbon were then determined using the calculated Boltzmann distributions, and compared to experimental chemical shifts to obtain the MAD for each compound studied.…”