Archive for November, 2012

Monosaccharides benchmark

A comprehensive evaluation of how different computational methods perform in predicting the energies of monosaccharides comes to some very interesting conclusions. Sameera and Pantazis1 have examined the eight different aldohexoses (allose, alltrose, glucose, mannose, gulose, idose, galactose and talose), specifically looking at different rotomers of the hydroxymethyl group, α- vs. β-anomers, pyranose vs. furanose isomers, ring conformations (1C4 vs skew boat forms), and ring vs. open chain isomers. In total, 58 different structures were examined. The benchmark computations are CCSD(T)/CBS single point energies using the SCS-MP2/def2-TZVPP optimized geometries. The RMS deviation from these benchmark energies for some of the many different methods examined are listed in Table 1.

Table 1. Average RMS errors (kJ mol-1) of the 58 different monosaccharide structures for
different computational methods.


average RMS error























Perhaps the most interesting take-home message is that CEPA, MP2, the double hybrid methods and M06-2x all do a very good job at evaluating the energies of the carbohydrates. Given the significant computational advantage of M06-2x over these other methods, this seems to be the functional of choice! The poorer performance of the DFT methods over the ab initio methods is primarily in the relative energies of the open-chain isomers, where errors can be on the order of 10-20 kJ mol-1 with most of the functionals; even the best overall methods (M06-2x and the double hybrids) have errors in the relative energies of the open-chain isomers of 7 kJ mol-1. This might be an area of further functional development to probe better treatment of the open-chain aldehydes vs. the ring hemiacetals.


(1) Sameera, W. M. C.; Pantazis, D. A. "A Hierarchy of Methods for the Energetically Accurate Modeling of Isomerism in Monosaccharides," J. Chem. Theory Comput. 2012, 8, 2630-2645, DOI:10.1021/ct3002305

DFT &sugars Steven Bachrach 28 Nov 2012 No Comments

Hacking…or how I spent my Thanksgiving vacation

I have long been a proponent of the Internet as holding the potential for revolutionizing how chemists communicate. This blog represents one of the ways that electronic communication can enhance how we exchange ideas.

This blog began as a means for me to maintain the currency of my book Computational Organic Chemistry. I realized that as soon as the book was physically printed and distributed, it was already 6 months out of date, and every subsequent day the book became that much less current. But the blog provides a mechanism for me to continuously provide updates to the book. As new articles are published, I can comment on them with the same perspective as I brought to the book.

I have been blogging now for over 5 years: almost 300 posts discussing well over 300 new articles relevant to computational organic chemistry. While the number of comments and commenters has not been particularly large, many of these comments are quite astute and there has been the occasional quite interesting back-and-forth discussion.

While my blogging is not entirely altruistically motivated, this has been more of a labor of love than anything else. So one might understand my dismay when about two weeks ago I received email messages from Jan and Henry and Eugene telling me that when they tried to access the blog, their browsers came back with a malware notice message from Google. Apparently Google will scan sites for problems and most current browsers will poll Google for the health of these sites prior to actually connecting to them.

My blog became infected somehow, and now I had to figure out how to remove the infestation! Fortunately, my son is a CS guru and so when I visited him for the Thanksgiving weekend we set out to disinfect the wordpress installation. After a bit of poking around, we found that every css file associated with the theme had unauthorized byte-code. Once we removed all of that, we submitted the site for review by Google, but to no avail – the site was still infected. So, back to more searching and we discovered that many of the plugins were infected, as were other themes. So another round of removing the foreign code and resubmittal to Google, and finally we passed inspection. The blog is now running clean!

But what a pain! And all for some junk that simply referred people to other sites. This headache cost a number of hours of searching and cleaning and worrying – for no good reason at all. (And I had a free software consultant – Thanks D!) I must say that I came seriously close to deciding to chuck the blog entirely. The hassle of maintaining the site and fighting off spammers and the like are truly the seamy side of the web. If one ever hears the comment that distributing information on the net is “free” – remind them of the constant vigilance needed to ward off spammers and hackers and other vermin. And my little site is nowhere near as vital or subject to attack as say a bank, or a military base, or even a scientific publisher.

I appreciate more now the true cost of doing business on the web. I dismay about the future – the web is very much the “wild west” and lawlessness pervades. I worry that I (and others) may finally just give up. I wish I knew of a solution, but I realize that there is no way to perfectly secure a site.

So if anyone out there has a WordPress site and gets infected I can offer some advice for cleansing – and if anyone has advise as to how to stem the malware tide, please share!

E-publishing Steven Bachrach 27 Nov 2012 4 Comments

Computed C-C NMR coupling constants

The use of computed NMR coupling constants is starting to grow. In a previous post I discussed a general study by Rablen and Bally on methods for computing JHH coupling constants. Now Williamson reports methods to experimentally obtain 1 JCC and 3JCC coupling constants.1 These were obtained for strychnine. He then computed the coupling constants in two steps. Using the B3LYP/6-31G(d) optimized geometry, first the Fermi contact contribution was computed at B3LYP/6-31+G(d,p) by uncontracting the basis set and adding an additional tighter set of polarization functions. Second, the remaining terms (spin-dipolar, paramagnetic spin-orbit and diamagnetic spin-orbit coupling) were computed with the 6-31+Gd,p) set without modifications. The two computed terms were added to give the final estimate.

A plot of the experimental vs. the DFT computed 1 JCC and 3JCC coupling constants shows
an excellent linear relation, with correlation coefficient of 0.9986 and a slope of 0.98. The mean absolute deviation for the computed and experimental 1 JCC and 3JCC coupling constants is 1.0
Hz and 0.4 Hz, respectively, both well within the experimental error.

I expect that computed NMR spectra will continue to be a growth area, especially for structural identification.


(1) Williamson, R. T.; Buevich, A. V.; Martin, G. E. "Experimental and Theoretical Investigation of 1JCC and nJCC Coupling Constants in Strychnine," Org. Letters 2012, 14, 5098-5101, DOI: 10.1021/ol302366s



NMR Steven Bachrach 14 Nov 2012 3 Comments

Assessing aromaticity

Assessing the degree of aromaticity in a novel compound has been a much sought after prize, and is the topic of much of Chapter 2 in my book. An interesting approach is described in a recent JACS paper by Williams and Mitchell.1 The interior methyl groups of 1 sit above and below the ring plane of the aromatic dihydropyrene and provide an interesting magnetic probe of the aromaticity; the chemical shift of these methyl groups are δ -4.06ppm, far upfield as they sit in the shielded region above the aromatic plane. Annelation of a benzene ring to give 2 should reduce the ring current, thereby reflecting a reduced aromatic character. In fact, the chemical shifts of the methyls in 2 are δ -1.58 ppm. This relatively large chemical shift difference provides a means for measuring the aromatic influence of other fused rings.



Suppose a different (non-benzene) ring were fused onto 1. Williams and Mitchell examined two such cases 3 and 4 (among others). These two compounds were prepared and studied by 1H NMR and also by B3LYP/6-31G* computations. The optimized structures of 3 and 4 are shown in Figure 1.



The experimental chemical shifts of the interior methyl groups are δ -3.32 ppm. This downfield shift of the methyls relative to their position in 1 reflects some homoaromatic character of the cycloheptatrienyl ring. If we take the difference in the methyl chemical shifts in 1 and 2 to reflect the aromatic character of benzene (2.48 ppm), then the difference in the chemical shifts of 3 and 1 (0.74 ppm) indicates that the cycloheptatrienyl ring has 0.74/2.48*100 = 30% the (homo)aromatic character of benzene! Similarly, the methyl chemical shifts in 4 are δ -3.56 ppm, leading to an estimate of the aromatic character of the tropone ring of 20%.



Figure 1. B3LYP/6-31G* optimized geometries of 3 and 4.

In using NICS to estimate the aromatic character, they make use of the average value of the NICS in the four rings of the dihydropyrene fragment. The baseline comparison is then in the average NICS value of 1 compared to that in 5, a compound that has a similar geometry but without the aromatic character of the fused benzene ring. This difference is 11.42ppm. The analogous relationship is then 3 with 6 (a NICS difference of 3.81 ppm) and 4 with 7 (a NICS difference of 2.77ppm). This gives an estimate of the (homo)aromatic character of cycloheptatriene of 33% and the aromatic character of tropolone of 24%. This NICS estimates are in great agreement with the experimental values from the proton chemical shifts.





(1) Williams, R. V.; Edwards, W. D.; Zhang, P.; Berg, D. J.; Mitchell, R. H. "Experimental Verification of the Homoaromaticity of 1,3,5-Cycloheptatriene and Evaluation of the Aromaticity of Tropone and the Tropylium Cation by Use of the Dimethyldihydropyrene Probe," J. Am. Chem. Soc. 2012, 134, 16742-16752, DOI: 10.1021/ja306868r.


1: InChI=1S/C26H32/c1-23(2,3)21-13-17-9-11-19-15-22(24(4,5)6)16-20-12-10-18(14-21)25(17,7)26(19,20)8/h9-16H,1-8H3/t25-,26-

2: InChI=1S/C30H34/c1-27(2,3)21-15-19-13-14-20-16-22(28(4,5)6)18-26-24-12-10-9-11-23(24)25(17-21)29(19,7)30(20,26)8/h9-18H,1-8H3/t29-,30-/m1/s1

3: InChI=1S/C33H40/c1-20-13-21(2)15-27-26(14-20)28-18-24(30(3,4)5)16-22-11-12-23-17-25(31(6,7)8)19-29(27)33(23,10)32(22,28)9/h11-12,14-19H,13H2,1-10H3/t32-,33-/m1/s1

4: InChI=1S/C33H38O/c1-19-13-25-26(14-20(2)29(19)34)28-18-24(31(6,7)8)16-22-12-11-21-15-23(30(3,4)5)17-27(25)32(21,9)33(22,28)10/h11-18H,1-10H3/t32-,33-/m1/s1

Aromaticity Steven Bachrach 07 Nov 2012 No Comments