Archive for July, 2017

Structure of GlyGly

Continuing their application of laser ablation molecular beam Fourier transform microwave (LA-MB-FTMW) spectroscopy and computational chemistry to biochemical molecules (see these previous posts), the Alonso group reports on the structure of the glycine-glycine dipeptide 1.1 The microwave spectrum shows three different conformers. MP2/6-311++G(d,p) computations, the same method they have previously utilized for predicting geometries, revealed a number of different conformations. By matching the spectroscopic parameters obtained from the spectrum with those of the computed structures, they proposed the three conformations 1a, 1b, and 1c, shown in Figure 1.




Figure 1. ωb97xd/6-31G(d) optimized structures of the three conformers of 1.
Note that the authors did not report their structures in their supporting materials(!) so I have optimized them.

The structures of conformers 1a and 1b are nearly planar. MP2 predicts a non-planar rotomer of 1a, which brings the carboxyl group out of plane, to be the lowest conformation in terms of electronic energy. With the M06-2x functional, this non-planar rotomer is about isoenergetic with 1a. With all computational levels 1a is the lowest in free energy. The barrier for rotation between the non-planar rotomer and 1a is very small, and this explains why it is not observed in the supersonic expansion.


1) Cabezas, C.; Varela, M.; Alonso, J. L., "The Structure of the Elusive Simplest Dipeptide Gly-Gly." Angew. Chem. Int. Ed. 2017, 56, 6420-6425, DOI: 10.1002/anie.201702425.


1: InChI=1S/C4H8N2O3/c5-1-3(7)6-2-4(8)9/h1-2,5H2,(H,6,7)(H,8,9)

amino acids Steven Bachrach 17 Jul 2017 No Comments

Another procedure for computing NMR chemical shifts

Here’s another take on automating a procedure for using computer 13C chemical shifts to assess chemical structure.1 (Have a look at these previous posts for some alternative methods and applications.) The approach here is to benchmark a few computational methods against a conformationally flexible drug-like molecule, in this case 1. A variety of conformations were optimized using the different computational methods, and 13C chemical shifts evaluated from a Boltzmann-weighted distribution. While the best agreement with the experimental chemical shifts (based on the root-mean-squared deviation) is with ωB97XD/cc-pVDZ, the authors opt for B3LYP/cc-pVDZ for its computational efficiency with only slightly poorer performance. (It should be note that WC04/cc-pVDZ, a functional designed for computing 13 chemical shifts,2 is almost as good as ωB97XD/cc-pVDZ. Also, not mentioned in the article is the dramatically poorer performance of the pcS-2 basis set, despite the fact that it was parametrized3 for NMR computation!)

They apply the procedure to a number of test cases. For example, the HIV-1 reverse transcriptase inhibitor nevirapine hydrolyzes to a compound whose structure has been difficult to identify. The four proposed structures 2a-d were subjected to the computational method, and the 13C chemical shift RMSD for 2d is only 2.3ppm, significantly smaller than for the other 3 structures. Compound 2d was then synthesized and its NMR matches that of the nevirapine hydrolysis product.


1) Xin, D.; Sader, C. A.; Chaudhary, O.; Jones, P.-J.; Wagner, K.; Tautermann, C. S.; Yang, Z.; Busacca, C. A.; Saraceno, R. A.; Fandrick, K. R.; Gonnella, N. C.; Horspool, K.; Hansen, G.; Senanayake, C. H., "Development of a 13C NMR Chemical Shift Prediction Procedure Using B3LYP/cc-pVDZ and Empirically Derived Systematic Error Correction Terms: A Computational Small Molecule Structure Elucidation Method." J. Org. Chem. 2017, ASAP, DOI: 10.1021/acs.joc.7b00321.

2) Wiitala, K. W.; Hoye, T. R.; Cramer, C. J., “Hybrid Density Functional Methods Empirically Optimized for the Computation of 13C and 1H Chemical Shifts in Chloroform Solution,” J. Chem. Theory Comput. 2006, 2, 1085-1092, DOI: 10.1021/ct6001016.

3) Jensen, F., “Basis Set Convergence of Nuclear Magnetic Shielding Constants Calculated by Density Functional Methods,” J. Chem. Theory Comput., 2008, 4, 719-727, DOI: 10.1021/ct800013z.


1: InChI=1S/C24H26F4N2O4S/c1-4-35(33,34)18-7-8-20-15(10-18)9-17(30-20)13-23(32,24(26,27)28)22(2,3)12-14-5-6-16(25)11-19(14)21(29)31/h5-11,30,32H,4,12-13H2,1-3H3,(H2,29,31)/t23-/m0/s1

2d: InChI=1S/C15H16N4O2/c1-9-6-8-17-14(18-10-4-5-10)12(9)19-13-11(15(20)21)3-2-7-16-13/h2-3,6-8,10H,4-5H2,1H3,(H,16,19)(H,17,18)(H,20,21)

NMR Steven Bachrach 10 Jul 2017 No Comments