Archive for December, 2013

Gas phase structure of 2-deoxyribose

2-deoxyribose 1 is undoubtedly one of the most important sugars as it is incorporated into the backbone of DNA. The conformational landscape of 1 is complicated: it can exist as an open chain, as a five-member ring (furanose), or a six-member ring (pyranose), and intramolecular hydrogen bonding can occur. This internal hydrogen bonding is in competition with hydrogen bonding to water in aqueous solution. Unraveling all this is of great interest in predicting structures of this and a whole host of sugar and sugar containing-molecules.


In order to get a firm starting point, the gas phase structures of the low energy conformers of 1 would constitute a great set of structures to use as a benchmark for gauging force fields and computational methods. Cocinero and Alonso1 have performed a laser ablation molecular beam Fourier transform microwave (LA-MB-FTMW) experiment (see these posts for other studies using this technique) on 1 and identified the experimental conformations by comparison to structures obtained at MP2/6-311++G(d,p). Unfortunately the authors do not include these structures in their supporting materials, so I have optimized the low energy conformers of 1 at ωB97X-D/6-31G(d) and they are shown in Figure 1.

1a (0.0)

1b (4.7)

1c (3.3)

1d (5.6)

1e (8.9)

1f (9.4)

Figure 1. ωB97X-D/6-31G(d) optimized structures of the six lowest energy conformers of 1. Relative free energy in kJ mol-1.

The computed spectroscopic parameters were used to identify the structures responsible for the six different ribose conformers observed in the microwave experiment. To give a sense of the agreement between the computed and experimental parameters, I show these values for the two lowest energy conformers in Table 1.

Table 1. MP2/6-311++G(d,p) computed and observed spectroscopic parameters for the two lowest energy conformers of 1.














B (MHz)





C (MHz)





ΔG (kJ mol-1)





This is yet another excellent example of the symbiotic relationship between experiment and computation in structure identification.


(1) Peña, I.; Cocinero, E. J.; Cabezas, C.; Lesarri, A.; Mata, S.; Écija, P.; Daly, A. M.; Cimas, Á.; Bermúdez, C.; Basterretxea, F. J.; Blanco, S.; Fernández, J. A.; López, J. C.; Castaño, F.; Alonso, J. L. "Six Pyranoside Forms of Free 2-Deoxy-D-ribose," Angew. Chem. Int. Ed. 2013, 52, 11840-11845, DOI: 10.1002/anie.201305589.


1a: InChI=1S/C5H10O4/c6-3-1-5(8)9-2-4(3)7/h3-8H,1-2H2/t3-,4+,5-/m0/s1

MP &sugars Steven Bachrach 16 Dec 2013 No Comments

Computation-aided structure determination

I have not discussed any papers that utilize computations to confirm chemical structure in a while, so here are two recent examples.

Grabow has utilized MP2 and M06-2x computations to confirm the lowest energy conformation of (-)-lupinine 1.1 The interesting structural aspect of this compound is the possibility of an intramolecular hydrogen bond linking the hydroxyl group with the amine.


Using molecular mechanics, the authors identified 57 structures within 50 kJ mol-1 of each other. These geometries were reoptimized at MP2/6-311++G(d,p) and M06-2x/6-311++G(d,p).
The lowest energy structures had the expected trans ring fusion, with a trans relationship between the hydrogen on the bridgehead carbon (C9) and the hydroxymethyl group. This corresponds to either the (R,R) or (S,S) isomer. The three lowest energy structures are shown in Figure 1. Unfortunately, the geometry for the lowest energy isomer provided in the Supporting Materials is wrong, and the authors did not supply the geometries of the other isomers. This situation is unacceptable! Reviewers and editors must do a better job in policing the Supporting Materials; there is no excuse for not including all of the optimized structures, and better yet, in a more usable format that what has been done here. I have reoptimized these structures at M06-2x/6-31G(d). The lowest energy conformer 1a does possess the expected internal hydrogen bond.




Figure 1. M06-2x/6-31G(d) optimized structures of the three lowest energy conformers of 1, with relative free energies in kJ mol-1.

Table 1 provides a comparison of the MP2 computed values of important structural parameters along with the experimental values obtained from a microwave experiment. The agreement with the computed values for 1a provides strong evidence that this is the structure of (-)-lupinine.

Table 1. Comparison of MP2 and experimental structural parameters of 1.a


Expt. (1)

MP2 (1a)




























aRotational constants (A, B, C) in MHz, centrifugal distortion constants (ΔJ, ΔJK, ΔK) in kHz, and nuclear quadrupole coupling tensor elements (χaa, χbb, χcc) in MHz.

The second study utilizes computed NMR chemical shifts to discriminate potential diastereomeric structures. Laurefurenyne A was first assigned the structure 2 based on 1D and 2D NMR experiments. However, based on potential biochemical analogy to other compounds, Paton and Burton2 had doubts about this structure. In addition to synthesizing the natural material, they performed an extensive computational study of the chemical shifts of the diastereomers. For each of the 32 possible diastereomers, they performed a Monte Carlo search of the conformational space using molecular mechanics. The structures of all isomers within 10 kJ mol-1 of the lowest energy structure were reoptimized at ωB97X-D/6-31G(d) with PCM (CHCl3) and chemical shifts obtained at mPW1PW91/6-311G(d,p). Final chemical shifts were obtained using a Boltzmann weighting. The computed values for 2 were quite off from the experimental values, with a mean unsigned error of 1.5 ppm. A better assessment was provided with the DP4 method, which indicated that 3 has the highest probability of being the correct structure, a structure consistent with the likely biosynthetic pathway.




(1) Jahn, M. K.; Dewald, D.; Vallejo-López, M.; Cocinero, E. J.; Lesarri, A.; Grabow, J.-U. "Rotational Spectra of Bicyclic Decanes: The Trans Conformation of (-)-Lupinine," J. Phys. Chem. A 2013, DOI: 10.1021/jp407671m.

(2) Shepherd, D. J.; Broadwith, P. A.; Dyson, B. S.; Paton, R. S.; Burton, J. W. "Structure Reassignment of Laurefurenynes A and B by Computation and Total Synthesis," Chem. Eur. J. 2013, 19, 12644-12648, DOI: 10.1002/chem.201302349.


(-)-Lupinine 1: InChI=1S/C11H21NO/c1-11-6-2-3-7-12(11)8-4-5-10(11)9-13/h10,13H,2-9H2,1H3/t10-,11+/m0/s1

Laurefurenyne A 3: InChI=1S/C14H20O4.C2H6/c1-3-4-5-6-12-11(16)8-14(18-12)13-7-10(15)9(2)17-13;1-2/h1,4-5,9-16H,6-8H2,2H3;1-2H3/b5-4-;/t9-,10-,11-,12+,13-,14+;/m1./s1

NMR Steven Bachrach 09 Dec 2013 2 Comments

Extrapolated CCSD(T) Thermochemistry

Suppose you are looking at the reaction aA + bB → cC + dD. You can compute each of these molecules at two computational levels; lets call these M1 and M2. Then the reaction energy is

ΔEM1 = cEM1(C) + dEM1(D) – aEM1(A) – bEM1(B)
ΔEM2 = cEM2(C) + dEM2(D) – aEM2(A) – bEM2(A)

Now, if the two computational methods are reasonably complete, then ΔEM1 ≈ ΔEM2. This can also be true if the reaction has been selected such that one might expect very good cancellation of errors. In this case, the overall problems in computing the reactants are similar to the problems computing the products, and so these problems (i.e., errors) will cancel off. So, if we have the latter condition (a reaction constructed to obtain excellent cancellation of errors), then we might be able to exploit this idea in order to obtain energies of large molecules with a large method while avoiding to actually have to do these very large computations!

How does this work? Let’s suppose the largest molecule in the reaction is molecule C. Since



cEM1(C) + dEM1(D) – aEM1(A) – bEM1(B) ≈ cEM2(C) + dEM2(D) – aEM2(A) – bEM2(B)

cEM1(C) ≈ cEM2(C) + d[EM2(D) – EM1(D)] – a[EM2(A) – EM1(A)] – b[EM2(B) – EM1(B)]

and so

cEM1(C) ≈ cEM2(C) + Σ ci(EM2(i) – EM1(i))

So, we can get the energy of the big molecule C at the big method M1 by computing the energy of the big molecule C at the smaller method M2 along with computing all of the other molecules at both levels. If these other molecules are significantly smaller than molecule C, there can be considerable time savings here. This is the idea presented in a recent article by Raghavachari.1

The key element here is a systematic means for generating appropriate reactions, ones that (a) involve small molecules other than the molecule of interest and (b) get good cancellation of errors. Raghavachari comes up with a systematic way of creating a reaction with ever larger reference molecules. This is analogous with the methodology presented by Wheeler, Schleyer and Allen.2 Basically, the method decomposes the molecule of interest into smaller molecules that preserve the immediate chemical environment around each heavy atom, a method they call CBH-2 (connectivity-based hierarchy). The reaction below is an example of the CBH-2 decomposition reaction for methionine. (Note that CBH-2 is essentially a homodesmotic reaction and CBH-3 is essentially the group equivalent reaction I defined years ago.3)

They apply the concept towards computing the energy of larger molecules (having 6-13 heavy atoms) at CCSD(T)/6-31+G(d,p) by only having to compute these large molecules at MP2/6-31+G(d,p). For a set of 30 molecules, the error in the energy of the extrapolated energy vs. the actual CCSD(T) energy is 0.35 kcal mol-1.

One of the advantages of this approach is that the small molecules are used over and over again, but they need be computed only twice, once at CCSD(T) and once at MP2.

This is certainly an approach that has been implicitly employed by many people for a long time, but here is made explicit and points towards ways to apply it even more widely.


(1) Ramabhadran, R. O.; Raghavachari, K. "Extrapolation to the Gold-Standard in Quantum Chemistry: Computationally Efficient and Accurate CCSD(T) Energies for Large Molecules Using an Automated Thermochemical Hierarchy," J. Chem. Theor. Comput. 2013, ASAP DOI: 10.1021/ct400465q.

(2) Wheeler, S. E.; Houk, K. N.; Schleyer, P. v. R.; Allen, W. D. “A Hierarchy of Homodesmotic Reactions for Thermochemistry,” J. Am. Chem. Soc. 2009, 131, 2547-2560, DOI: 10.1021/ja805843n.

(3) Bachrach, S. M. “The Group Equivalent Reaction: An Improved Method for Determining Ring Strain Energy,” J. Chem. Ed. 1990, 67, 907-908, DOI: 10.1021/ed067p90.

QM Method Steven Bachrach 02 Dec 2013 2 Comments