Archive for December, 2014

Two review articles for the general audience

In trying to clean up my in-box of articles for potential posts, I write here about two articles for a more general audience, authored by two of the major leaders in computational organic chemistry.

Ken Houk offers an overview of how computational simulation is a partner with experiment and theory in aiding and guiding our understanding of organic chemistry.1 The article is written for the non-specialist, really even more for the non-scientist. Ken describes how computations have helped understand relatively simple reactions like pericyclic reactions, that then get more subtle when torquoselection is considered, to metal-catalysis, to designed protein catalysts. If you are ever faced with discussing just what you do as a computational chemist at a cocktail party, this article is a great resource of how to explain our science to the interested lay audience.

Paul Schleyer adds a tutorial on transition state aromaticity.2 The authors discusses a variety of aromaticity measures (energetics, geometry, magnetic properties) that can be employed to analyze the nature of transition states, in addition to ground state molecules. This article provides a very clear description of the methods and a few examples. It is written for a more specialized audience than Houk’s article, but is nonetheless completely accessible to any chemist, even those with no computational background.


(1) Houk, K. N.; Liu, P. "Using Computational Chemistry to Understand & Discover Chemical Reactions," Daedalus 2014, 143, 49-66, DOI: 10.1162/DAED_a_00305.

(2) Schleyer, P. v. R.; Wu, J. I.; Cossio, F. P.; Fernandez, I. "Aromaticity in transition structures," Chem. Soc. Rev. 2014, 43, 4909-4921, DOI: 10.1039/C4CS00012A.

Houk &Schleyer Steven Bachrach 22 Dec 2014 No Comments


Three-dimensional objects can be projected into four-dimensional objects. So for example a cube can be projected into a hypercube, as in Scheme 1.

Scheme 1.

Pichierri proposes a hydrocarbon analogue of the hypercube. The critical decision is the connecting bridge between the outer (exploded) carbons. This distance is too long to be a single carbon-carbon bond. Pichierri opts to use ethynyl bridges, to give the hypercube 1.1

Now, unfortunately he does not supply any supporting materials. So I have reoptimized this Oh geometry at B3LYP/6-31G(d), and show this structure in Figure 1. Pichierri does not report much beyond the geometry of 1 and the perfluoronated analogue. One interesting property that might be of interest is the ring strain energy of 1, which I will not take up here.



But a question I will take up is just what bridges might serve to create the hydrocarbon hypercube. A more fundamental choice might be ethanyl bridges, to create 2. However, the Oh conformer of 2 has 13 imaginary frequencies at B3LYP/6-31G(d). Lowering the symmetry to D3 give a structure that has only real frequencies, and it’s shown in Figure 1. An interesting exercise is to ponder other choices of bridges, which I will leave for the reader.



Figure 1. B3LYP/6-31G(d) optimized structures of 1 and 2.
As always, be sure to click on the image to enable Jmol for interactive viewing of these interesting structures!


(1) Pichierri, F. "Hypercubane: DFT-based prediction of an Oh-symmetric double-shell hydrocarbon," Chem. Phys. Lett. 2014, 612, 198-202, DOI: j.cplett.2014.08.032.


1: InChI=1S/C40H24/c1-2-26-7-9-29-15-11-27-5-3-25(1)4-6-28-12-16-30(10-8-26)20-23-32(22-19-29)24-21-31(17-13-27,18-14-28)39-35(27)33(25)34(26)37(29,35)40(32,39)38(30,34)36(28,33)39/h1-24H

2: InChI=1S/C40H48/c1-2-26-7-9-29-15-11-27-5-3-25(1)4-6-28-12-16-30(10-8-26)20-23-32(22-19-29)24-21-31(17-13-27,18-14-28)39-35(27)33(25)34(26)37(29,35)40(32,39)38(30,34)36(28,33)39/h1-24H2

Uncategorized Steven Bachrach 15 Dec 2014 2 Comments

Structure of carbonic acid

I remain amazed at how regularly I read reports of structure determinations of what seem to be simple molecules, yet these structures have eluded determination for decades if not centuries. An example is the recently determined x-ray crystal structure of L-phenylalanine;1 who knew that growing these crystals would be so difficult?

The paper I want to discuss here is on the gas-phase structure of carbonic acid 1.2 Who would have thought that preparing a pure gas-phase sample would be so difficult? Schreiner and co-workers prepared carbonic acid by high-vacuum flash pyrolysis (HVFP) of di-tert-butyl carbonate, as shown in Scheme 1.

Scheme 1

Carbonic acid can appear in three difference conformations, shown in Figure 1. The two lowest energy conformations are separated by a barrier of 9.5 kcal mol-1 (estimated by focal point energy analysis). These conformations can be interconverted using near IR light. The third conformation is energetically inaccessible.






Figure 1. CCSD(T)/cc-pVQZ optimized structures of 1 (and the focal point relative energies in kcal mol-1) and the CCSD(T)/cc-pVTZ optimized structures of 2.

The structures of these two lowest energy conformations were confirmed by comparing their experimental IR spectra with the computed spectra (CCSD(T)/cc-pVTZ) and their experimental and computed rotational constants.

An interesting added component of this paper is that sublimation of the α- and β-polymorphs of carbonic acid do not produce the same compound. Sublimation of the β-isomorph does produce 1, but sublimation of the α-isomorph produces the methylester of 1, compound 2 (see Figure 1). The structure of 2 is again confirmed by comparison of the experimental and computed IR spectra.


(1) Ihlefeldt, F. S.; Pettersen, F. B.; von Bonin, A.; Zawadzka, M.; Görbitz, C. H. "The Polymorphs of L-Phenylalanine," Angew. Chem. Int. Ed. 2014, 53, 13600–13604, DOI: 10.1002/anie.201406886.

(2) Reisenauer, H. P.; Wagner, J. P.; Schreiner, P. R. "Gas-Phase Preparation of Carbonic Acid and Its Monomethyl Ester," Angew. Chem. Int. Ed. 2014, 53, 11766-11771, DOI: 10.1002/anie.201406969.>


1: InChI=1S/CH2O3/c2-1(3)4/h(H2,2,3,4)

2: InChI=1S/C2H4O3/c1-5-2(3)4/h1H3,(H,3,4)

Schreiner Steven Bachrach 09 Dec 2014 1 Comment

Paul Schleyer: In Memorium

Professor Paul von Ragué Schleyer passed away November 21, 2014. Paul was a major force in physical organic and computational organic chemistry. I followed his career closely for the entirety of my own career; my doctoral studies with Andrew Streitwieser involved the analysis of the nature of the C-Li bond and we were in constant communication with Schleyer. Paul’s work on aromaticity greatly informed my thinking and my studies in this area.

I interviewed Paul in his office at the University of Georgia for the first edition of my book Computational Organic Chemistry. This interview was reprinted in the second edition without any changes. In honor of Paul, I am posting this interview here, so that our community can remember this important, inspirational figure.



Interview: Professor Paul von Ragué Schleyer

Interviewed March 28, 2006

Professor Paul Schleyer is the Graham Perdue Professor of Chemistry at the University of Georgia, where he has been for the past 8 years. Prior to that, he was a professor at the University at Erlangen (co-director of the Organic Institute) and the founding director of its Computer Chemistry Center. Schleyer began his academic career at Princeton University.

Professor Schleyer’s involvement in computational chemistry dates back to the 1960s, when his group was performing MM and semi-empirical computations as an adjunct to his predominantly experimental research program. This situation dramatically changed when Professor John Pople invited Schleyer to visit Carnegie-Mellon University in 1969 as the NSF Center of Excellence Lecturer. From discussions with Dr. Pople, it became clear to Schleyer that “ab initio methods could look at controversial subjects like the nonclassical carbocations. I became hooked on it!” The collaboration between Pople and Schleyer that originated from that visit lasted well over 20 years, and covered such topics as substituent effects, unusual structures that Schleyer terms “rule-breaking”, and organolithium chemistry. This collaboration started while Schleyer was at Princeton but continued after his move to Erlangen, where Pople came to visit many times. The collaboration was certainly of peers. “It would be unfair to say that the ideas came from me, but it’s clear that the projects we worked on would not have been chosen by Pople. Pople added a great deal of insight and he would advise me on what was computationally possible,” Schleyer recalls of this fruitful relationship.

Schleyer quickly became enamored with the power of ab initio computations to tackle interesting organic problems. His enthusiasm for computational chemistry eventually led to his decision to move to Erlangen – they offered unlimited (24/7) computer time, while Princeton’s counteroffer was just 2 hours of computer time per week. He left Erlangen in 1998 due to enforced retirement. However, his adjunct status at the University of Georgia allowed for a smooth transition back to the United States, where he now enjoys a very productive collaborative relationship with Professor Fritz Schaefer.

Perhaps the problem that best represents how Schleyer exploits the power of ab initio computational chemistry is the question of how to define and measure aromaticity. Schleyer’s interest in the concept of aromaticity spans his entire career. He was drawn to this problem because of the pervasive nature of aromaticity across organic chemistry. Schleyer describes his motivation: “Aromaticity is a central theme of organic chemistry. It is re-examined by each generation of chemists. Changing technology permits that re-examination to occur.” His direct involvement came about by Kutzelnigg’s development of a computer code to calculate chemical shifts. Schleyer began use of this program in the 1980s and applied it first to structural problems. His group “discovered in this manner many experimental structures that were incorrect.”

To assess aromaticity, Schleyer first computed the lithium chemical shifts in complexes formed between lithium cation and the hydrocarbon of interest. The lithium cation would typically reside above the aromatic ring and its chemical shift would be affected by the magnetic field of the ring. While this met with some success, Schleyer was frustrated by the fact that lithium was often not positioned especially near the ring, let alone in the center of the ring. This led to the development of nucleus-independent chemical shift (NICS), where the virtual chemical shift can be computed at any point in space. Schleyer advocated using the geometric center of the ring, then later a point 1 Å above the ring center.

Over time, Schleyer came to refine the use of NICS, advocating an examination of NICS values on a grid of points. His most recent paper posits using just the component of the chemical shift tensor perpendicular to the ring evaluated at the center of the ring. This evolution reflects Schleyer’s continuing pursuit of a simple measure of aromaticity. “Our endeavor from the beginning was to select one NICS point that we could say characterizes the compound,” Schleyer says. “The problem is that chemists want a number which they can associate with a phenomenon rather than a picture. The problem with NICS was that it was not soundly based conceptually from the beginning because cyclic electron delocalization-induced ring current was not expressed solely perpendicular to the ring. It’s only that component which is related to aromaticity.”

The majority of our discussion revolved around the definition of aromaticity. Schleyer argues that “aromaticity can be defined perfectly well. It is the manifestation of cyclic electron delocalization which is expressed in various ways. The problem with aromaticity comes in its quantitative definition. How big is the aromaticity of a particular molecule? We can answer this using some properties. One of my objectives is to see whether these various quantities are related to one another. That, I think, is still an open question.”

Schleyer further detailed this thought, “The difficulty in writing about aromaticity is that it is encrusted by two centuries of tradition, which you cannot avoid. You have to stress the interplay of the phenomena. Energetic properties are most important, but you need to keep in mind that aromaticity is only 5% of the total energy. But if you want to get as close to the phenomenon as possible, then one has to go to the property most closely related, which is magnetic properties.” This is why he focuses upon the use of NICS as an aromaticity measure. He is quite confident in his new NICS measure employing the perpendicular component of the chemical shift tensor. “This new criteria is very satisfactory,” he says. “Most people who propose alternative measures do not do the careful step of evaluating them against some basic standard. We evaluate against aromatic stabilization energies.”

Schleyer notes that his evaluation of the aromatic stabilization energy of benzene is larger than many other estimates. This results from the fact that, in his opinion, “all traditional equations for its determination use tainted molecules. Cyclohexene is tainted by hyperconjugation of about 10 kcal mol-1. Even cyclohexane is very tainted, in this case by 1,3-interactions.” An analogous complaint can be made about the methods Schleyer himself employs: NICS is evaluated at some arbitrary point or arbitrary set of points, the block-diagonalized “cyclohexatriene” molecule is a gedanken molecule. When pressed on what then to use as a reference that is not ‘tainted’, Schleyer made this trenchant comment: “What we are trying to measure is virtual. Aromaticity, like almost all concepts in organic chemistry, is virtual. They’re not measurable. You can’t measure atomic charges within a molecule. Hyperconjugation, electronegativity, everything is in this sort of virtual category. Chemists live in a virtual world. But science moves to higher degrees of refinement.” Despite its inherent ‘virtual’ nature, “Aromaticity has this 200 year history. Chemists are interested in the unusual stability and reactivity associated with aromatic molecules. The term survives, and remains an enormously fruitful area of research.”

His interest in the annulenes is a natural extension of the quest for understanding aromaticity. Schleyer was particularly drawn to [18]-annulene because it can express the same D6h symmetry as does benzene. His computed chemical shifts for the D6h structure differed significantly from the experimental values, indicating that the structure was clearly wrong. “It was an amazing computational exercise,” Schleyer mused, “because practically every level you used to optimize the geometry gave a different structure. MP2 overshot the aromaticity, HF and B3LYP undershot it. Empirically, we had to find a level that worked. This was not very intellectually satisfying but was a pragmatic solution.” Schleyer expected a lot of flak from crystallographers about this result, but in fact none occurred. He hopes that the x-ray structure will be re-done at some point.

Reflecting on the progress of computational chemistry, Schleyer recalls that “physical organic chemists were actually antagonistic toward computational chemistry at the beginning. One of my friends said that he thought I had gone mad. In addition, most theoreticians disdained me as a black-box user.” In those early years as a computational chemist, Schleyer felt disenfranchised from the physical organic chemistry community. Only slowly has he felt accepted back into this camp. “Physical organic chemists have adopted computational chemistry; perhaps, I hope to think, due to my example demonstrating what can be done. If you can show people that you can compute chemical properties, like chemical shifts to an accuracy that is useful, computed structures that are better than experiment, then they get the word sooner or later that maybe you’d better do some calculations.” In fact, Schleyer considers this to be his greatest contribution to science – demonstrating by his own example the importance of computational chemistry towards solving relevant chemical problems. He cites his role in helping to establish the Journal of Computational Chemistry in both giving name to the discipline and stature to its practitioners.

Schleyer looks to the future of computational chemistry residing in the breadth of the periodic table. “Computational work has concentrated on one element, namely carbon,” Schleyer says. “The rest of the periodic table is waiting to be explored.” On the other hand, he is dismayed by the state of research at universities. In his opinion, “the function of universities is to do pure research, not to do applied research. Pure research will not be carried out at any other location.” Schleyer sums up his position this way – “Pure research is like putting money in the bank. Applied research is taking the money out.” According to this motto, Schleyer’s account is very much in the black.

Reprinted from Computational Organic Chemistry, Steven M. Bachrach, 2014, Wiley:Hoboken.


Schleyer Steven Bachrach 02 Dec 2014 2 Comments

Structure of Histidine

The Alonso group has yet again (see these posts) determined the gas-phase structure of an important, biologically significant molecule using a combination of exquisite microwave spectroscopy and quantum computations. This time they examine the structure of histidine.1

They optimized four conformations of histidine, as its neutral tautomer, at MP2/6-311++G(d,p). These are schematically drawn in Figure 1. Conformer 1a is the lowest in free energy, likely due to the two internal hydrogen bonds. Its structure is shown in Figure 2.

Figure 1. The four conformers of histidine. The relative free energy (MP2/6-311++G(d,p)) in kcal mol-1 are also indicated.

Figure 2. MP2/6-311++G(d,p) optimized geometry of 1a.

The initial experimental rotation constants were only able to eliminate 1b from consideration. So they then determined the quadrupole coupling constants for the 14N nuclei. These values strongly implicated 1a as the only structure in the gas phase. The agreement between the experimental values and the computed values at MP2/6-311++G(d,p) was a concern, so they rotated the amine group to try to match the experimental values. This lead to a change in the NHCC dihedral value of -16° to -23° Reoptimization of the structure at MP2/cc-pVTZ led to a dihedral of -21° and overall excellent agreement between the experimental spectral parameters and the computed values.

It is somewhat disappointing the supporting materials does not include the structures of the other three isomers, nor the optimized geometry at MP2/cc-pVTZ.


1) Bermúdez, C.; Mata, S.; Cabezas, C.; Alonso, J. L. "Tautomerism in Neutral Histidine," Angew. Chem. Int. Ed. 2014, 53, 11015-11018, DOI: 10.1002/anie.201405347.


Histidine: InChI=1S/C6H9N3O2/c7-5(6(10)11)1-4-2-8-3-9-4/h2-3,5H,1,7H2,(H,8,9)(H,10,11)/t5-/m0/s1

amino acids Steven Bachrach 01 Dec 2014 No Comments