Molecular structures can differ depending on phase, particularly between the gas and solution phase. Kass has looked at the protonation of 4-aminobenzoic acid. In water, the amino is its most basic site, but what is it in the gas phase? The computed relative energies of the protonation sites are listed in Table 1. If one corrects the B3LYP values for their errors in predicting the proton affinity of aniline and benzoic acid, the carbonyl oxygen is predicted to be the most basic site by 5.0 kcal mol^-1, in nice accord with the G3 prediction of 4.1 kcal mol^-1. Clearly, the structure depends on the medium.

Table 1. Computed relative proton affinities (kcal mol^-1) of 4-aminobenzoic acid.

Electrospray of 4-aminobenzoic acid from 3:1 methanol/water and 1:1 acetonitrile/water solutions gave different CID spectra. H/D exchange confirmed that electrospray from the emthanol/water solution gave the oxygen protonated species while that from the acetonitrile/water solution gave the ammonium species.

References

(1) Tian, Z.; Kass, S. R., “Gas-Phase versus Liquid-Phase Structures by Electrospray Ionization Mass Spectrometry,” Angew. Chem. Int. Ed., 2009, 48, 1321-1323, DOI: 10.1002/anie.200805392.

InChIs

4-aminobenzoic acid: InChI=1/C7H7NO2/c8-6-3-1-5(2-4-6)7(9)10/h1-4H,8H2,(H,9,10)/f/h9H
InChIKey=ALYNCZNDIQEVRV-BGGKNDAXCD

One more nail in the coffin of the widely disputed Le Clair structure of hexacyclinol is provided by the B97-2/cc-pVTZ/B3LYP/6-31G(d,p) computed proton and ¹³C NMR for the two “structures” (see my previous blog post for structures and background). These computations¹ are at a more rigorous level than those performed by Rychnovsky, and the addition of the proton spectrum helps clearly settle this issue. Rychnovsky’s structure is the correct one – the mean absolute error between the experimental and computed structure is half that for Rychnovsky structure. The computed coupling constants also are in much better agreement with the Rychnovsky structure. So, Bagno’s contribution accomplishes, I hope, two things: (1) convinces everyone that DFT NMR spectra can be an important tool in identifying natural product structure and (2) closes the book on hexacylinol!

References

(1) Saielli, G.; Bagno, A., "Can Two Molecules Have the Same NMR Spectrum? Hexacyclinol Revisited," Org. Lett. 2009, 11, 1409-1412, DOI: 10.1021/ol900164a.

The paper I will discuss here is a bit afield from computational organic chemistry, but it raises some interesting issues that tangentially touch on the main theme of my blog.

Roger Sayle of OpenEye describes a software tool for translating chemical names from one language into another, for example a name in English to the corresponding name in German or Japanese or Chinese.¹ One might imagine the many difficulties in this process – the strong dependency on very minor changes in the name can mean substantially different chemicals (think of propane vs. propene vs. propyne vs. propanol vs. propanal vs. propenal, etc.) and all this needs to be carefully recognized and translated.

My interest here is that chemical names including IUPAC names are really not the lingua franca of chemistry. Yes, chemists do use names but we really rely most on chemical structure drawings – that’s the surest way of transmitting our meaning to one another. But images are not a very good way for computers to communicate meaning. And that’s where the InChI label steps in. InChIs provide a standard means for two chemists (or two computers) to exchange chemical information without introducing errors and without the need for an intervening third-party to guarantee the meaning.

Here is a simple example of the benefit of the InChI using the first example from Sayle’s article. Figure 1 in his paper has the two similarly names compounds phenylacetate 1 and phenyl acetate 2. Note the critical importance of the blank space (actually this blank space is omitted in Figure 1 of the paper indicating just how easy it is for errors to sneak in!). Sayle points out that many languages beside English do not make use of whitespace in the way that English does, so that this translation must be done with special care.

Now the InChIs of 1 and 2 are unambiguous and will be the same in all (human) languages, eliminating the need of translation concerns. And if you’re unhappy with the length of the InChI, the InChIKey provides a fixed length string that captures almost all of the information of the InChI itself.

All compounds mentioned in my blog are listed at the end with their InChIs to promote the exchange of information and to encourage search-and-retrieval through the web. The leader in this sort of technology has been the Chemspider site, and I urge you to explore it and the use of InChIs.

As an aside, for all you Star Trek nerds, the paper includes this quote

and includes a reference to the Klingon Language Institute! This just might be the first time Klingon has appeared in a chemistry journal!

References

(1) Sayle, R., "Foreign Language Translation of Chemical Nomenclature by Computer," J. Chem. Inf. Model. 2009, DOI: 10.1021/ci800243w.

What is the rate determining step in the Hajos-Parrish-Eder-Sauer-Wiechert reaction (reaction 1)? This basic question of the mechanism for the first example of the use of proline as a catalyst remains unanswered, though a recent paper by Meyer and Houk¹ does moves us forward.

Their ¹³C kinetic isotope effect study revealed that only the nucleophilic ketone (the carboyl of the butyl chain) experiences any significant effect, with a value of about 1.03. B3LYP/6-31G(d,p) computations of the three transition states shown below were performed for both the gas phase and solution using IEF-PCM. Calculations of the transition state for the formation of the C-C bond (TS3) predicts no kinetic isotope effect, indicating that it is not the rate limiting step, in conflict with previous² suggestions. The transition states for the formation of the carbinolamine (TS1) and formation of the iminium (TS2) both predict an isotope effect comparable with experiment. TS1 is about 3 kcal mol^-1 higher in energy than TS2. The authors conclude that a step prior to formation of the C-C is the rate limiting step of the Hajos-Parrish-Eder-Sauer-Wiechert reaction, but cannot discern between the two possibilities examined.

References

(1) Zhu, H.; Clemente, F. R.; Houk, K. N.; Meyer, M. P., "Rate Limiting Step Precedes C-C Bond Formation in the Archetypical Proline-Catalyzed Intramolecular Aldol Reaction," J. Am. Chem. Soc., 2009, 131, 1632-1633, DOI: 10.1021/ja806672y.

(2) Clemente, F. R.; Houk, K. N., "Computational Evidence for the Enamine
Mechanism of Intramolecular Aldol Reactions Catalyzed by Proline," Angew. Chem. Int. Ed., 2004, 43, 5766-5768, DOI: 10.1002/anie.200460916.

InChIs

2-methyl-2-(3-oxobutyl)cyclopentane-1,3-dione:
InChI=1/C10H14O3/c1-7(11)5-6-10(2)8(12)3-4-9(10)13/h3-6H2,1-2H3
InChIKey=OZBYSCPBJGAYMQ-UHFFFAOYAW

(3aS,7aS)-3a-hydroxy-7a-methyl-3,4,6,7-tetrahydro-2H-indene-1,5-dione:
InChI=1/C10H14O3/c1-9-4-2-7(11)6-10(9,13)5-3-8(9)12/h13H,2-6H2,1H3/t9-,10+/m1/s1
InChIKey=PUHCDQVSBDIJTM-ZJUUUORDBA

Following on their prediction that the thiol of cysteine¹ is more acidic than the carboxylic acid group (see this post), Kass has examined the acidity of tyrosine 1.² Which is more acidic: the hydroxyl (leading to the phenoxide 2) or the carboxyl (leading to the carboxylate 3) proton?

Kass optimized the structures of tyrosine and its two possible conjugate bases at B3LYP/aug-cc-pVDZ, shown in Figure 1, and also computed their energies at G3B3. 2 is predicted to be 0.2 kcal mol^-1 lower in energy than 3 at B3LYP and slightly more stable at G3B3 (0.5 kcal mol^-1). However, both computational methods underestimate the acidity of acetic acid more than that of phenol. When the deprotonation energies are corrected for this error, the phenolic proton is predicted to be 0.4 kcal mol^-1 more acidic than the carboxylate proton at B3LYP and 0.9 kcal mol^-1 more acidic at G3B3.

1
2	3

Figure 1. B3LYP/aug-cc-pVDZ optimized structures of tyrosine 1 and its two conjugate bases 2 and 3.²

Gas phase experiments indicate that deprotonation of tyrosine leads to a 70:30 mixture of the phenoxide to carboxylate anions. The computations are in nice agreement with this experiment. (A Boltzmann weighting of the computed lowest energy conformers makes only a small difference to the distribution relative to using simply the single lowest energy conformer.) This demonstrates once again the important role of solvent, since only the carboxylate anion is seen in aqueous solution.

References

(1) Tian, Z.; Pawlow, A.; Poutsma, J. C.; Kass, S. R., "Are Carboxyl Groups the Most Acidic Sites in Amino Acids? Gas-Phase Acidity, H/D Exchange Experiments, and Computations on Cysteine and Its Conjugate Base," J. Am. Chem. Soc., 2007, 129, 5403-5407, DOI: 10.1021/ja0666194.

(2) Tian, Z.; Wang, X.-B.; Wang, L.-S.; Kass, S. R., "Are Carboxyl Groups the Most Acidic Sites in Amino Acids? Gas-Phase Acidities, Photoelectron Spectra, and Computations on Tyrosine, p-Hydroxybenzoic Acid, and Their Conjugate Bases," J. Am. Chem. Soc., 2009, 131, 1174-1181, DOI: 10.1021/ja807982k.

InChIs

1: InChI=1/C9H11NO3/c10-8(9(12)13)5-6-1-3-7(11)4-2-6/h1-4,8,11H,5,10H2,(H,12,13)/t8-/m0/s1/f/h12H
InChIKey=OUYCCCASQSFEME-QAXLLPJCDY

2: InChI=1/C9H11NO3/c10-8(9(12)13)5-6-1-3-7(11)4-2-6/h1-4,8,11H,5,10H2,(H,12,13)/p-1/t8-/m0/s1/fC9H10NO3/q-1
InChIKey=OUYCCCASQSFEME-HVHKCMLZDU

3: InChI=1/C9H11NO3/c10-8(9(12)13)5-6-1-3-7(11)4-2-6/h1-4,8,11H,5,10H2,(H,12,13)/p-1/t8-/m0/s1/fC9H10NO3/h11h,12H/q-1
InChIKey=OUYCCCASQSFEME-XGYCJDCADS