Archive for October, 2010

Computing anions with DFT

Computing anions have long been understood to offer interesting challenges. For example, anions require diffuse functions for reasonable description. Jensen1 has now investigated the electron affinity of atoms and small molecules with three DFT methods: BHHLYP having 50% HF and 50% Becke exchange, B3LYP having 20% HF and 80% Becke exchange and BLYP with 100% Becke exchange. The result is that all three express varying degrees of electron loss from the atom or molecule in the anion. Thus the anionic species really possess only fractional anionic charge.

In cation-anion pairs or in large species that have strong electron acceptors and donors (say a protein), this electron loss manifests itself in less ionic character than what should actually be present. In other words density is erroneously moved off of the anionic center and transferred to the cationic center.

This error is due to poor description of the long-range exchange. Including the LC correction does eliminate the problem, and so one should be very careful in using DFT for anions.


(1) Jensen, F., "Describing Anions by Density Functional Theory: Fractional Electron Affinity," J. Chem. Theory Comput., 2010, 6, 2726-2735, DOI: 10.1021/ct1003324

DFT Steven Bachrach 26 Oct 2010 6 Comments

Heavy-atom tunneling confirmed

Borden predicted measurable heavy-atom isotope effects in the ring opening of cyclopropylcarbinyl radical. In my blog post on this paper, I concluded with the line:

Borden hopes that experimentalists will reinvestigate this
problem (and hopefully confirm his predictions).

Well, in a recent paper where Borden collaborates with Singleton, these predictions are confirmed!1

There is a sizable kinetic isotope effect for breaking the ring bond to a 12C over a bond to a 13C atom, up to 16% at -100 °C. The KIE predicted without including tunneling are dramatically below the experimental values, but incorporation of tunneling in the computated KIEs match up with experiment with an error no greater that 0.7%. The Arrhenius plot of ln KIE vs. 1/T shows enhanced isotope effects when tunneling is included, very nice agreement between the experimental and tunneling-corrected KIEs and curvature – all indicative of heavy atom tunneling. Lastly, the ring open product (1-butene) is the observed major product (62%) at -100 °C; the minor product is methylcyclopropane. In the absence of heavy-atom tunneling, 1-butene would be the minor product (28%).


(1) Gonzalez-James, O. M.; Zhang, X.; Datta, A.; Hrovat, D. A.; Borden, W. T.; Singleton, D. A. J. Am. Chem. Soc., 2010, 132, 12548-12549, DOI: 10.1021/ja1055593.


Cyclopropylcarbonyl radical: InChI=1/C4H7/c1-4-2-3-4/h4H,1-3H2

1-butene: InChI=1/C4H8/c1-3-4-2/h3H,1,4H2,2H3

Borden &Singleton &Tunneling Steven Bachrach 22 Oct 2010 1 Comment

Acidity of lithium acetylide

I have had a long-standing interest in organolithium compounds, dating back to my graduate student days. Thus, I was excited to read Kass and Radom’s latest work on the computational and experimental evaluation of the acidity of lithium acetylide LiCCH.1

The gas phase experimental acidity is accomplished by preparing the conjugate base of lithium acetylide through a procedure of collision-induced dissociation with loss of CO2, as in Scheme 1. By reacting this anion with a variety of different acids, they were able to bracket the acidity and determine that ΔHacid is 391.0 ± 1.3 kcal mol-1. This is about 13 kcal mol-1 less acidic than acetylene itself. The reduction is acidity understandable in terms of the C-Li being essentially ionic, and thereby loss of the proton builds up negative charge on a carbon adjacent to a carbon that already has a great deal of negative charge.

Scheme 1

Computations support this enthalpy for deprotonation. The G3, G4 and W1 values for the enthalpy deprotonation of lithium acetylide are 389.1, 388.9, and 390.4 kcal mol-1, respectively. It should also be noted that the conjugate base of lithium acetylide posses a non-classical bridging geometry 1, which is well-known for organolithium species.2


(1) Meyer, M. M.; Chan, B.; Radom, L.; Kass, S., R., "Gas-Phase Synthesis and Reactivity of Lithium Acetylide Ion, LiCC-," Angew. Chem. Int. Ed., 2010, 49, 5161-5164, DOI: 10.1002/anie.201001485

(2) Streitwieser, A.; Bachrach, S. M.; Dorigo, A.; Schleyer, P. v. R. In Lithium Chemistry: A Theoretical and Experimental Overview; Sapse, A.-M., Schleyer, P. v. R., Eds.; Wiley-Interscience: New York, 1995, p 1-45.

Acidity &Kass Steven Bachrach 18 Oct 2010 No Comments

Dipeptide structure: computation and experiment

Here’s a nice example of the productive interplay between experiment and computations.1 The dipeptide N-Acyl-Ala-Ala-Benzyl was prepared and subjected to UV and IR/UV analysis. The IR showed two separate structures with distinctly different environments for the NH bonds: one structure showed intramolecular hydrogen bonding while the other did not.

B97/TZVPP computations revealed two structures. The first is a linear dipeptide with intramolecular hydrogen bonding occurring in a 5,5 relationship. (There are actually three conformers of this but all have similar energy, only one is shown in Figure 1.) The second structure displays a bent shape with a NH-π interaction, also shown in Figure 1. The computed vibrational spectra for each structure matches up well with the NH region of the experimental IR.

Figure 1. B97-D/TZVPP optimized structures of N-Acyl-Ala-Ala-Benzyl.

The authors spend a great deal of time noting that the 0 K energies predict that the second structure, being 4 kcal mol-1 more stable, should be the only one observed. However, since the jet cooling will likely trap the structures at their 300 K distribution, this could account for the existence of two structures. However, when the computations include entropy corrections, so now we’re looking at ΔG(200 K), B97-D and MO6-2x suggest that the two structures are very close in energy. But they caution that MP2 predicts a large energy gap unless atomic counterpoise corrections are used to account for intramolecular basis set superposition (see this post), a problem that appears to be much less severe with the DFT methods.


(1) Gloaguen, E.; de Courcy, B.; Piquemal, J. P.; Pilme, J.; Parisel, O.; Pollet, R.; Biswal, H. S.; Piuzzi, F.; Tardivel, B.; Broquier, M.; Mons, M. J. Am. Chem. Soc, 2010, 132, 11860-11863, DOI: 10.1021/ja103996q



amino acids Steven Bachrach 12 Oct 2010 1 Comment

Oxazolidinone intermediates in proline-catalyzed aldol reactions?

The proline-catalyzed aldol reaction is discussed in Chapter 5.3 of my book. This is an area of continued research and the recent paper of Sharma and Sunoj addresses an alternative mechanism involving oxazolidinone.1 They examine the proline-catalyzed aldol self-condensation of propanal with B3LYP/6-31+G** and MP2/6-31+G** computations. This reaction is found to proceed2 with 4:1 anti:syn diastereoselectivity.

An oxazolidinone intermediate has been observed in proline-catalyzed aldol condensations. This intermediate is proposed to come about via Path b, whereas the generally accepted mechanism put forth by Houk and List, discussed in my book, follows Path a. Sharma and Sunoj find that the oxazolidinone 7 is lower in energy than the enamine 4, and its barrier for ring opening back to 3 is large. Thus, it is not unreasonable that it is the observed intermediate.

Gas phase computations of the reaction of 4 to 5 predict a 99% ee and an anti:syn ratio of about 5:1, in nice agreement with experiment. However, incorporation of solvent reduces the ration to 2:1, and the MP2 computations give a ratio of 1.2:1, in even worse agreement with experiment. However, the major predicted product has the same absolute configuration as the observed product.

The other mechanism is examined in the key step 8 to 9. Here all computations predict that syn addition is favored over anti addition and the enantiomer of the experimentally observed product is predicted to be formed. In addition, intermediate 9 and the TSs leading to it are much higher in energy than intermediate 5 and the TSs associated with its formation. Thus, the oxazolidinone addition mechanism is discounted.


(1) Sharma, A.; Sunoj, R., "Enamine versus Oxazolidinone: What Controls Stereoselectivity in Proline-Catalyzed Asymmetric Aldol Reactions?," Angew. Chem. Int. Ed., 2010, 49, 6373-6377, DOI: 10.1002/anie.201001588

(2) Northrup, A. B.; MacMillan, D. W. C., "The First Direct and Enantioselective Cross-Aldol Reaction of Aldehydes," J. Am. Chem. Soc., 2002, 124, 6798-6799, DOI: 10.1021/ja0262378

aldol Steven Bachrach 05 Oct 2010 1 Comment