Archive for June, 2016

Predicting chemical structure using DP4+

Structure determination has been greatly facilitated by the use of computed NMR spectra to compare with experimental spectra. Perhaps the best method for doing this is the DP4 procedure developed by Smith and Goodman.1 (I have a previous post on their paper.) The basic idea is that if you have an experimental NMR spectrum and a number of potential structures, the computed spectra for each possibility are ranked by a statistical treatment based on the Student t-test.

Grimblat, Zanardi, and Sarotti question a couple of the assumptions embedded within the DP4 method, and offer a revision that they call DP4+.2 The two assumptions are (1) that the chemical shifts are computed at B3LYP/6-31G**//MMFF and (2) that the chemical shifts are scaled and then utilized in the analysis.

To test these assumptions, they examine a set of 72 organic compounds comprising 1219 13C shifts and 1123 1H shifts. They optimized the structures at B3LYP/6-31G* and computed the chemical shifts of these compounds using the B3LYP and mPW1PW91 functionals with 6 basis sets (6-31G*, 6-31G**, 6-31+G**, 6-311G*, 6-311G**, and 6-311+G**). With all of the combinations, the standard deviation of both the proton and carbon chemical shifts were significantly smaller than with the originally proposed method.

With regards to the second assumption, they define a new probability functions that multiplies the error using scaled chemical shifts with the error using unscaled chemical shifts, and this they call DP4+. Again with all of the computational methods, the DP4+ prediction outperforms the DP4 prediction.

As a test case, they looked at cryptomoscatone D1 and D2 (1), for which the structures were determined with traditional methods. DP4 predicts that both cryptomoscatone D1 and D2 are structure 1d. However, DP4+ correctly predicts that cryptomoscatone D1 is 1b and cryptomoscatone D2 is 1a.

Lin and Tagliatatela-Scafati have reported the use of DP4+ to aid in the structure determination of plakdiepoxide 2.3 ROESY NMR could not provide definitive judgement of the stereochemical relationship about the bond between the two epoxide rings. They computed a number of conformers of the model compounds 2a and 2b at B3LYP/6-31G(d). The computed chemical shifts were then used with the DP4+ procedure to determine that the structure has the stereochemistry of 2b.


(1) Smith, S. G.; Goodman, J. M. "Assigning Stereochemistry to Single Diastereoisomers by GIAO NMR Calculation: The DP4 Probability," J. Am. Chem. Soc. 2010, 132, 12946-12959, DOI: 10.1021/ja105035r.

(2) Grimblat, N.; Zanardi, M. M.; Sarotti, A. M. "Beyond DP4: an Improved Probability
for the Stereochemical Assignment of Isomeric Compounds using Quantum Chemical Calculations of NMR Shifts," J. Org. Chem. 2015, 80, 12526-12534, DOI: 10.1021/acs.joc.5b02396.

(3) Chianese, G.; Yu, H.-B.; Yang, F.; Sirignano, C.; Luciano, P.; Han, B.-N.; Khan, S.; Lin, H.-W.; Taglialatela-Scafati, O. "PPAR Modulating Polyketides from a Chinese Plakortis simplex and Clues on the Origin of Their Chemodiversity," J. Org. Chem. 2016, 81 (12), 5135–5143, DOI: 10.1021/acs.joc.6b00695.


Cryptomoscatone D1: InChI=1S/C17H20O4/c18-14(10-9-13-5-2-1-3-6-13)11-15(19)12-16-7-4-8-17(20)21-16/h1-6,8-10,14-16,18-19H,7,11-12H2/b10-9+/t14-,15-,16-/m1/s1

Cryptomoscatone D2: InChI=1S/C17H20O4/c18-14(10-9-13-5-2-1-3-6-13)11-15(19)12-16-7-4-8-17(20)21-16/h1-6,8-10,14-16,18-19H,7,11-12H2/b10-9+/t14-,15+,16+/m0/s1

plakdiepoxide: InChI=1S/C18H32O4/c1-6-9-10-13(4)12-17(7-2)16(22-17)18(8-3)14(21-18)11-15(19)20-5/h13-14,16H,6-12H2,1-5H3/t13?,14-,16-,17+,18-/m0/s1

NMR Steven Bachrach 20 Jun 2016 1 Comment

Mechanism of dimethyldioxirane oxidation

Dimethyldioxirane can oxidize alkanes to alcohols. The mechanism for the oxidation has been controversial, ranging from concerted, to radical intermediates to an H-abstraction—O-rebound mechanism. Yang, Yu, and Houk now offer a molecular dynamics examination of the reaction of dimethyldioxirane with isobutane.1

Gas–phase (U)B3LYP/6-311++G(d,p)//(U)B3LYP/6-31G(d) computations give critical points outlined in the reaction below. The structures of the transition states and the intermediate are shown in Figure 1.




Figure 1. (U)B3LYP/6-31G(d) optimized geometries of TS1, INT, and TS2. Relative free energies (kcal mol-1) in the gas (top) and solution (bottom) phases

The PES indicates a rebound mechanism, though in acetone solution phase, there was no transition state located for the second step; it appears to be barrierless. It should be noted that the size of the barrier is very small even in the gas phase. The energy given in Figure 1 is for the gas phase structure computed in solution.

Trajectories for both gas and solution phase were computed. For the gas phase, about 90% of the trajectories lead to separated radicals, but in an acetone about 90% of the trajectories lead directly to the alcohol, with only 10% leading to radicals. Even so, the acetone trajectories divide into two types, a dynamically concerted path where the time gap between the formation of the new C-O and O-H bonds is less than 60 fs, and a dynamically stepwise path where the time gap is greater than 60 fs, though for the trajectories that lead to product the gap is typically still less than 150 fs.


(1)  Yang, Z.; Yu, P.; Houk, K. N. "Molecular Dynamics of Dimethyldioxirane C–H Oxidation," J. Am. Chem. Soc. 2016, 138, 4237-4242, DOI: 10.1021/jacs.6b01028.


Dimethyldioxirane: InChI=1S/C3H6O2/c1-3(2)4-5-3/h1-2H3

Isobutane: InChI=1S/C4H10/c1-4(2)3/h4H,1-3H3

Houk Steven Bachrach 06 Jun 2016 No Comments