Archive for January, 2011

Aromaticity of azines

How is the aromaticity of benzene affected by nitrogen substitution? Are pyridine and pyrimidine more or less aromatic than benzene? This question has been addressed many times, and Schleyer adds to this discussion with a B3LYP/6-311+G** study of the entire series of azines.1 Analysis of the aromaticity is based on a two metrics: NICS(0)πzz and extra cyclic resonance energy (ECRE). The NICS(0) πzz value is now the ring current measurement advocated by Schleyer as it only includes the π orbitals and uses the tensor component perpendicular to the ring. ECRE is obtained by comparing block-localized energies of the azine to appropriate acyclic references.

Interestingly, both metrics give the same result, namely, that the aromaticity of benzene and all of the azines 1-6 are essentially equally aromatic.


(1) Wang, Y.; Wu, J. I. C.; Li, Q.; Schleyer, P. v. R., "Aromaticity and Relative Stabilities of Azines," Org. Lett., 2010, 12, 4824-4827, DOI: 10.1021/ol102012d


1: InChI=1/C5H5N/c1-2-4-6-5-3-1/h1-5H

2a: InChI=1/C4H4N2/c1-2-4-6-5-3-1/h1-4H

2b: InChI=1/C4H4N2/c1-2-5-4-6-3-1/h1-4H

2c: InChI=1/C4H4N2/c1-2-6-4-3-5-1/h1-4H

3a: InChI=1/C3H3N3/c1-2-4-6-5-3-1/h1-3H

3b: InChI=1/C3H3N3/c1-2-5-6-3-4-1/h1-3H

3c: InChI=1/C3H3N3/c1-4-2-6-3-5-1/h1-3H

4a: InChI=1/C2H2N4/c1-2-4-6-5-3-1/h1-2H

4b: InChI=1/C2H2N4/c1-3-2-5-6-4-1/h1-2H

4c: InChI=1/C2H2N4/c1-3-5-2-6-4-1/h1-2H

5: InChI=1/CHN5/c1-2-4-6-5-3-1/h1H

6: InChI=1/N6/c1-2-4-6-5-3-1

Aromaticity &Schleyer Steven Bachrach 25 Jan 2011 No Comments

Has a cyclobutadiene species been isolated? (Part 2)

Henry Rzepa’s response1 to the reported detection and x-ray structure of 1,3-dimethylcyclobutadiene2 has now been published. He takes a different tack than those take by Alabugin3 and Scheschkewitz4 in refuting the analysis of this work (see this earlier post). Rzepa discuses computations to evaluate the possible lifetime of 1,3-dimethylcyclobutadiene in the vicinity of CO2. In particular, he examines the barrier for the allowed [4+2] cycloaddition to give back the lactone 1 (Reaction 1), which was photolyzed in the experiment to produce the cyclobutadiene and CO2 species in the first place.

Reaction 1

The gas phase free energy barrier at 175 K (the experimental condition) computed at ωB97XD/6-311G(d,p) is 16.8 kcal mol-1, which is sufficiently high to limit this back reaction. Embedding this into a water continuum lowers the barrier to 12.9 kcal mol-1.

But the experiment has these species embedded inside a calixarene host along with guanidinum
cations. The cation could associate with the CO2 (indicated in Reaction 1 as X), and inclusion of a guanidinium in the gas phase, reduces the barrier to 3.3 kcal mol-1. Rerunning this computation now with a water continuum produce an intermediate zwitterion formed by making the C-C bond, and the second step makes the C-O bond.

Finally, modeling the reaction with guanidium inside a calixarene host leads to a barrier of 8 kcal
mol-1, 10.5 kcal mol-1 with water continuum. Rzepa concludes that recombination of 1,3-dimethylcyclobutadiene and CO2 to give 1 should be too fast on the timescale of the experiment for observation of the cyclobutadiene. This argument, along with the two previous papers, strongly casts doubt on the original claim.

I should point out that Henry has deposited all the structures in a nice enhanced table. You may need a subscription to get to this – I have not checked the access conditions.


(1) Rzepa, H. S., "Can 1,3-dimethylcyclobutadiene and carbon dioxide co-exist inside
a supramolecular cavity?," Chem. Commun. 2011, ASAP, DOI: 10.1039/C0CC04023A

(2) Legrand, Y.-M.; van der Lee, A.; Barboiu, M., "Single-Crystal X-ray Structure of 1,3-Dimethylcyclobutadiene by Confinement in a Crystalline Matrix," Science 2010, 329, 299-302, DOI: 10.1126/science.1188002.

(3) Alabugin, I. V.; Gold, B.; Shatruk, M.; Kovnir, K., "Comment on "Single-Crystal X-ray Structure of 1,3-Dimethylcyclobutadiene by Confinement in a Crystalline Matrix"," Science, 2010, 330, 1047, DOI: 10.1126/science.1196188.

(4) Scheschkewitz, D., "Comment on "Single-Crystal X-ray Structure of 1,3-Dimethylcyclobutadiene by Confinement in a Crystalline Matrix"," Science, 2010, 330, 1047, DOI: 10.1126/science.1195752.


1: InChI=1/C7H8O2/c1-4-3-7(2)5(4)6(8)9-7/h3,5H,1-2H3

1,3-dimethylcyclobutadiene: InChI=1/C6H8/c1-5-3-6(2)4-5/h3-4H,1-2H3

cyclobutadiene Steven Bachrach 18 Jan 2011 No Comments

News from Science Online 2011

I just attended Science Online 2011, an “unconference” that focuses on online tools and resources for science, especially in the social media aspect of science. A great deal of the discussions related to communication of science to the non-science community, with calls for more activism and clear voices to articulate the actions and processes of science clearly to the lay audience.

For the more technical minded, there were a few discussions of open data, data sharing, open notebook science and the like.

The conference was wonderfully organized in a great located (the Sigma Xi building in the Research Triangle Park). Bora and Anton are to be congratulated for putting together a meeting the way most of us want to have meetings – reasonably priced, meals included, buses to a from the hotels and venues, lots of time to mingle and talk, real discussion inside the sessions, etc.

Nonetheless, I came away from the meeting more depressed than when I arrived. This is a conference with a lot of younger people – I was amongst the old crowd. But I was really struck by a couple of attitudes that were quite pervasive in the rooms.

First, many people were advocating for open data and data sharing – admirable goals that I fully support. But the driving force was to make the data discoverable through Google – a decidedly non-Open organization. I was surprised by the complete capitulation to the edifice of Google. I was amazed that so many scientists (along with a slew of science journalists) who believed that Google was the way to search for science and information. In chemistry, this is so clearly not true, as specialized databases provide much better information, faster and cleaner than Google or Bing. Relying on a commercial service that is inherently not designed with science information in mind seems doomed from the start. Google is not going to be the tool for doing a substructure search. Furthermore, over the past couple of years I feel that Google has lost its mojo – when was the last time you were excited by a Google product? Google wave? and look where that is now…

Second, I was really struck once again by the very different practices, concerns, and cultures within the different disciplines of science. What chemists are doing and thinking and what they need is different than the biologists and the physicists and the geoscientists, etc. Solutions in one area will not necessarily transcribe over to another. We chemists should be thinking about what the web technologies can do for us and work for us. We might want to glance a peak at what are brethren are up to, but only for ideas and not as models to emulate.

The last observation is really much more pessimistic. I was greatly taken by the lack of risk-taking being expressed by so many people in the crowd. Academics young and old were advising to be careful with your blogging, tenure and promotion is solely driven by publications and grants, worry about a comment leading to some sort of retribution. People were advocating for the anonymous comment, the pseudonym-using blogger as a way of protecting oneself from the unnamed backlash that would destroy a career. Would we accept a journal that published articles with no attribution of the authors? Then why are we able to accept a comment to an article without an attribution? I was amazed at the view that science research communication tis solely through the journal – no thoughts on alternatives, no impetus to use new media to change how scholarly research is being conducted (except of course by the very small number of Open Notebook Science people at the meeting!). The status quo is well entrenched today and I worry that with the attitude expressed by younger scientists here, that we are doomed to continue these practices in the future. Now there was some undercurrent of distress that the current system was not ideal, but the lack of desire to take a risk, to put yourself out there, to express an opinion, to do something different means, I worry, that when these folks are tenured and in a position of more security they will continue to advise the next generation to act the same way.

We are the ones that run science. If we as community want to communicate and collaborate in different ways than that within the entrenched community, then we need to make it happen. Where are the risk-takers, those willing to stand up and say “we need to change. The old models no longer are serving us. We need to use (twitter, blogs, enhanced media, video, data sharing, open source software, etc) to enable our science – to bring disparate groups together to solve important problems. And we will make this happen.”

Uncategorized Steven Bachrach 17 Jan 2011 3 Comments

Conformers of Alanine

Small energy differences pose a serious challenge for computation. The focal point analysis of Allen and Schaefer is one approach towards solving this problem, with energies extrapolated to the complete basis set limit at the HF and MP2 levels, and then corrections added on for higher-order effects.

These authors have applied the method to the conformations of alanine (similar to their previous study on cysteine – see this post).1 There are two low energy conformers 1 and 2. The CCSD(T)/cc-pVTZ structures are shown in Figure 1. The HF/CBS estimate places 2 below 1, but this is reveres at MP2. With the correction for CCSD and CCSD(T), and core electrons, the energy gap is only 0.45 kJ mol-1, favoring 1. Zero-point vibrational energy favors 1 by 1.66 kJ mol-1, for a prediction that 1 is 2.11 kJ mol-1 lower in energy than 2. It is interesting that most of this energy difference arises from differences in their ZPVE.



Figure 1. CCSD(T)/cc-pVTZ optimized geometries of the two lowest energy conformations of alanine.

The article also discusses the structures of these to conformers, obtained through a combination of theoretical treatment and revisiting the limited experimental measurements.


(1) Jaeger, H. M.; Schaefer, H. F.; Demaison, J.; Csaszar, A. G.; Allen, W. D., "Lowest-Lying Conformers of Alanine: Pushing Theory to Ascertain Precise Energetics and Semiexperimental Re Structures," J. Chem. Theory Comput., 2010, 6, 3066-3078, DOI: 10.1021/ct1000236


Alanine: InChI=1/C3H7NO2/c1-2(4)3(5)6/h2H,4H2,1H3,(H,5,6)/t2-/m0/s1/f/h5H

amino acids &Schaefer Steven Bachrach 11 Jan 2011 No Comments

Definition of the hydrogen bond

An IUPAC commission has delivered a technical report on the definition of the hydrogen bond. Unfortunately, it does not as yet seem to be available through Pure and Applied Chemistry, but one of its lead authors, Gautum Desiraju, has written a personal perspective in the first issue of this year’s Angewandte Chemie.1

Hydrogen bonding may be to some extent within the eye of the beholder. If the “hydrogen bond” is worth less than a single kcal mol-1, how does that really differ from van der Waals interactions or London dispersion? If the interaction is upwards to 40 kcal mol-1, do we benefit from not simply calling that a bond? Further complexity comes in the nature of the hydrogen bond: is it simply strong dipole-dipole attraction? Does it possess some covalent character? What is its dispersion component? And can it have some charge transfer character? Is it perhaps some or all of these? Or does the particular environment dictate the nature?

Desiraju argues really for as broad a swath as possible, and the new definition borrows from Pauling’s original definition:

Under certain conditions an atom of hydrogen is attracted by rather strong forces to two atoms, instead of only one, so that it may be considered to be acting as a bond between them

ads in a dash of the Pimentel and McClellan definition:

(1) There is evidence of a bonds and (2) there is evidence that this bond specifically involves a hydrogen atom already bonded to another atom

to come up with

The hydrogen bond is an attractive interaction between a hydrogen atom from a molecule or molecular fragment X-H in which X is more electronegative than H, and an atom or a group of atoms in the same or different molecule, in which there is evidence of bond formation. A typical hydrogen bond may be depicted as X-HY-Z, where the three dots denote the bond. X-H represents the hydrogen bond donor. The acceptor may be an atom or an anion Y or a fragment or molecule Y-Z, where Y is bonded to Z. In specific cases X and Y can be the same with both X-H and Y-H bonds being equal. In any event, the acceptor is an electron-rich region such as, but not limited to, a lone pair in Y or a π-bonded pair in Y-Z.

Broad enough to cover just about everything! But it demands “evidence of bond formation” and the commission spells out a series of experiments/computations that might provide this evidence. One might wonder if this list is acceptable and complete.

While I think this is an interesting and necessary step forward, debate on hydrogen bonding is sure to rage on!


(1) Desiraju, G. R., "A Bond by Any Other Name," Angew. Chem. Int. Ed. 2011, 50, 52-59, DOI: 10.1002/anie.201002960

Uncategorized Steven Bachrach 06 Jan 2011 1 Comment

Interacting bis-allyl diradicals

Interacting bis-allyl radicals are the topic of a computational study by Gleiter and Borden.1 The new twist is to have the two allyl groups interact through a cyclobutyl, cyclopentyl or cyclohexyl ring, as in 1-3.

The degree of interaction of the radical electrons is evaluated with a number of metrics. First, the singlet-triplet energy gap is computed at CASSCF(6,6)/6-31G(d) and UB3LYP/6-31G(d). A larger gap is suggestive of strong interaction between the two allyl radicals. Next, the <S2> value of the UB3LYP wavefunction will be 0 for a pure singlet, which occurs when the radicals are strongly interacting. A value near 1 suggests an electron localized into each allyl fragment. Lastly, the natural orbital occupation numbers (NOON) of the two highest lying orbitals would be 2 and 0 for the pure interacting state and each would be 1 for the non-interacting state. The B3LYP/6-31G(d) optimized geometries of 1-3 are shown in Figure 1. The values of each metric are listed in Table 1.




Figure 1. B3LYP/6-31G(d) optimized geometries of 1-3.

Table 1. Metrics for evaluating the allyl interaction in 1-3.










1.62, 0.38





1.31, 0.69





1.20, 0.80

The different metrics are all consistent. The allyl radicals are strongly interacting in 1, with a low lying singlet state. The interaction is significantly lessened in 2 and smaller still in 3. The authors argue these differences in terms of the molecular orbital interactions between the allyl fragments and the central ring fragment.


(1) Lovitt, C. F.; Dong, H.; Hrovat, D. A.; Gleiter, R.; Borden, W. T., "Through-Bond Interactions in the Diradical Intermediates Formed in the Rearrangements of Bicyclo[n.m.0]alkatetraenes," J. Am. Chem. Soc., 2010, 132, 14617-14624, DOI: ja106329t


1: InChI=1/C10H10/c1-3-7-9-5-2-6-10(7)8(9)4-1/h1-10H

2: InChI=1/C11H12/c1-3-8-7-9-4-2-6-11(8)10(9)5-1/h1-6,8-11H,7H2

3: InChI=1/C12H14/c1-3-9-7-12-6-2-5-11(9)8-10(12)4-1/h1-6,9-12H,7-8H2

Borden &diradicals Steven Bachrach 04 Jan 2011 2 Comments