Alonso and coworkers have developed the technique of laser ablation molecular beam Fourier transform microwave spectroscopy to detect biomolecules. In a recent paper¹ they determined the structure of the glycine:one water complex – it is of the neutral configuration. They have now examined the conformations of cysteine². The presence of the thiol side group adds considerable complexity to the problem due to the many conformations possible.

The experiment detected six conformers. Determining the structures responsible for each set of signals was made possible by comparing the experimental results with those determined by computation. Alonso computed 11 low energy conformations of cysteine at MP2/6-311++G(d,p). Then comparing the computed rotational constants and ¹⁴N nuclear quadrupole coupling tensor components with the experiment, they were able to match up all six experimental conformers with computed structures. The experimental and computed constants for the three most abundant structures are listed in Table 1. The geometries of all six conformers are drawn in Figure 1.

Table 1.Experimental and computed spectroscopic constants (MHz) for the three most abundant conformers of cysteine.²

^aRelative energy in cm^-1 computed at MP4/6-311++G(d,p)// MP2/6-311++G(d,p).

IIb (0.0)	Ia (450)
Ib (325)	IIa (527)
IIIβc (765)	IIIβb (585)

Table 1. Optimized structures of the six observed conformers of cysteine. Relative energies in cm^-1 computed at MP4/6-311++G(d,p)//MP2/6-311++G(d,p). (Note – the geometries shown were optimized at PBE1PBE/6-311+G(d,p) since they MP2 structures are not available!)

This study demonstrates the nice complementary manner in which computation and experiment can work together in structure determination.

References

(1) Alonso, J. L.; Cocinero, E. J.; Lesarri, A.; Sanz, M. E.; López, J. C., "The Glycine-Water
Complex," Angew. Chem. Int. Ed. 2006, 45, 3471-3474, DOI: 10.1002/anie.200600342

(2) Sanz, M. E.; Blanco, S.; López, J. C.; Alonso, J. L., "Rotational Probes of Six Conformers of Neutral Cysteine," Angew. Chem. Int. Ed. 2008, DOI: 10.1002/anie.200801337

InChI

Cysteine: InChI=1/C3H7NO2S/c4-2(1-7)3(5)6/h2,7H,1,4H2,(H,5,6)/t2-/m0/s1
InChIKey: XUJNEKJLAYXESH-REOHCLBHBU

The very simple carbene hydroxymethylene, HOCH, has finally been prepared and characterized.¹ Glyoxylic acid CHOCO₂H is subjected to high-vacuum laser photolysis. It fragments into HOCH, which is then trapped into an argon matrix. The experimental IR frequencies match up very well with the CCSD(T)/cc-pVQZ harmonic frequencies of the trans isomer 1t that are also adjusted for anharmonic effects. The computed vertical excitation energy of 415 nm matches well with the experimental value of the maximum absorption in the UV/vis spectra of 427 nm.

The other very interesting experimental result is that HOCH has a lifetime of about 2 hours in the matrix, while the deuterated species DOCH is stable. To explain these results, Schreiner, Allen and co-workers optimized a number of structures on the PES at CCSD(T)/cc-pVQZ and computed their energies using the focal point technique. The optimized structures and their relative energies are given in Figure 1.

1t (0.0)	TS2 (29.7)	2 (-52.1)
TS1(26.8)
1c (4.4)

Figure 1. Optimized CCSD(T)/cc-pVQZ structures of HOCH isomers and their Focal Point relative energies (kcal mol^-1).¹

The barriers for rearrangement from 1t are both very high. Rearrangement to formaldehyde 2 requires crossing a barrier of 29.7 kcal mol^-1, while the barrier to convert to the cis isomer 1c is 26.8 kcal mol^-1. (Note that from 1c a cleavage into CO and H2 can occur, but this barrier is another 47.0 kcal mol^-1.) These barriers are too large to be crossed at the very low temperatures of the matrices. However, using the intrinsic reaction potential at CCSD(T)/cc-pVQZ and WKB theory, the tunneling lifetime of HOCH is computed to be 122 minutes, in excellent accord with the experiment. The lifetime for DOCH is computed to be over 1200 years. Thus, the degradation of hydroxymethylene is entirely due to tunneling through a very large classical barrier! This rapid tunneling casts serious doubt on the ability to ever identify any hydroxymethylene in interstellar space.

References

(1) Schreiner, P. R.; Reisenauer, H. P.; Pickard IV, F. C.; Simmonett, A. C.; Allen, W.
D.; Matyus, E.; Csaszar, A. G., "Capture of hydroxymethylene and its fast disappearance through tunnelling," Nature, 2008, 453, 906-909, DOI: 10.1038/nature07010.

InChI

1: InChI=1/CH2O/c1-2/h1-2H
2: InChI=1/CH2O/c1-2/h1H2

Here is another review of my book Computational Organic Chemistry; DOI: 10.1002/aoc.1406. This one is by John Brazier James Platts of Cardiff University and it appears in Applied Organometallic Chemistry. I do plead guilty to the charge of the interviews being USA-centric. This was due to scheduling problems that did not allow me to travel overseas.

Addicoat and Mehta¹ have made a modification of the “Kick” algorithm. Recall, that the Kick method (discussed in this previous blog post) takes a collection of atom coordinates and applies a random kick to each atom. This creates a new initial configuration and a geometry optimization is performed starting form this configuration. If hundreds of such configurations are chosen, one hopes to locate most if not all reasonable structures. The new variation is to create fragments in which the atoms are held fixed. Then the kick is applied to the fragment as a whole.

Among the examples demonstrated in the paper, only one is of an organic species. They examined the structure of the Gly-Trp peptide associated with two water molecules. They used two conformations of the Gly-Trp dipeptide. The kick was supplied to one of these conformers and to the two water molecules. They ended up locating 22 structures with the first conformer and 46 with the second, spanning a range of about 0.5 eV. It must be pointed out that many of these configurations are clearly noncompetitive by not maximizing the degree of hydrogen bonding that can be obtained. Furthermore, many other conformers of the dipeptide would need to be examined to really map out the full PES and definitively locate all reasonable low-energy configurations. (it is not necessary that the gas-phase low-energy conformers yield the lowest energy configurations of the water complex.) Nonetheless, this modified kick procedure offers a “quick-and-dirty” means of generating a wide variety of initial conditions for locating structures.

References

(1) Addicoat, M. A.; Metha, G. F., "Kick: Constraining a Stochastic Search Procedure with Molecular Fragments," J. Comput. Chem., 2008, DOI: 10.1002/jcc.21026

There remains still new territory to explore even with such well-known reactions as the Claisen rearrangement. Jacobsen reports a catalyzed Claisen rearrangement where the catalyst is urea-based.¹ Catalyst 1 produces modest to very reasonable % conversion in a series of simple Claisen rearrangements, as shown in Table 1.

Table 1. Claisen Rearrangements

With the chiral catalyst 2, the Claisen rearrangement is both catalyzed and proceeds with large enantiomeric excess, as shown in the representative example Reaction 1.

Jacobsen and Uyeda also reported the transition state for a model Claisen rearrangement catalyzed by a model guanidinium ion (Reaction 2) computed at B3LYP/6-31G(d). I have reproduced this calculation and the calculations for the both the catalyzed and uncatalyzed rearrangements, shown in Figure 1. In email communication with Dr. Jacobsen, I was able to confirm these energies against their own unpublished results.

Uncatalyzed Reaction 2
Reactant: 0.0	TS: 25.73
Product 1: -11.04	Product 2: -13.69
Catalyzed Reaction 2
Reactant: 0.0	TS: 21.09
Product 1: -12.36	Product 2: -12.80

Figure 1. B3LYP/6-31G(d) optimized structures of the critical points of uncatalyzed and catalyzed Reaction 2. Relative energies in kcal mol^-1.

The structures show the beneficial hydrogen bonds between the guanidinium anion and the carbonyl oxygens (or the ether oxygen of the reactant). In progressing from the transition state, both reactions first gives Product 1. This product conformer can than rotate to give the lower energy conformer Product 2. The activation energy of the catalyzed reaction is 4.64 kcal mol^-1 lower than for the uncatalyzed reaction, demonstrating the benefit of the complexation in the transition state.

I want to thank Dr. Jacobsen and his graduate student Chris Uyeda for sharing their computational results with me for the preparation of this blog post.

References

(1) Uyeda, C.; Jacobsen, E. N., "Enantioselective Claisen Rearrangements with a Hydrogen-Bond Donor Catalyst," J. Am. Chem. Soc., 2008, 130, 9228-9229, DOI: 10.1021/ja803370x.

A review of my book Computational Organic chemistry written by Christian Mück-Lichtenfeld, has appeared in Synthesis DOI: 10.1055/s-2008-1080541. A few things I particularly appreciate in the review is that Dr. Mück-Lichtenfeld recognized that the book in not intended to be a comprehensive review of computational organic chemistry but rather a survey of highlights, he mentions the book’s web site and blog, and favorably comments on the interviews that conclude each section.

What happens when anions are sequentially solvated with more and more water? In an interesting study by Chesnovsky, Gerber and coworkers, the answer is proton transfer!¹ They examined the conjugate base of aniline (C₆H₅NH^-, 1) using both PES and MP2/DZP computations. The PES spectrum of 1 shows two strong peaks. When this anion is then coordinates with one or two water molecules, C₆H₅NH^-)^.(H₂O) or (C₆H₅NH^-)^.(H₂O)₂, the peaks shifts to higher energy but the general shape remains unchanged. When three or more water molecules are coordinated to 1, the PE spectra totally changes, becoming broad and relatively featureless.

What accounts for this different PES? The authors posit that the PES of these larger clusters resembles that of hydrated OH^- clusters. Optimization of (C₆H₅NH^-)^.(H₂O) or (C₆H₅NH^-)^.(H₂O)₂
gave structures of the waters hydrogen bonded to the nitrogen anion. However, optimization of the (C₆H₅NH^-)^.(H₂O)₃ gave in fact a cluster of the form (C₆H₅NH₂)^.(HO^-)^.(H₂O)₂. The two lowest energy structures are shown in Figure 1. The structures correspond to the transfer of one proton from water to the anilinide anion to give aniline associated with hydroxide and two water molecules.

Rel E: 0.0

Rel E: 0.10 eV

Figure 1. B3LYP/6-31+G(d) optimized structures of
the C₆H₅NH₂)^.(HO^-)^.(H₂O)₂ clusters.

(Note: Once again the authors have failed to include the computed structures as part of the supporting information and so I have reoptimized the structures but at a lower, computationally more tractable level. Hopefully, authors, editors and reviewers will standardize this practice and include such materials in all papers in the very near future!)

Though aniline is a stronger gas-phase acid than water (DPE(aniline) = 366.4 kcal mol^-1 and DPE(H₂O) = 390.3 kcal mol^-1), the reverse is true in solution (pK_a(aniline) = 27.3) and pK_a(water) = 15.7). As more water molecules are present, the preferential solvation of the hydroxide anion over C₆H₅NH^- results in the formation of hydroxide.

References

(1) Wolf, I.; Shapira, A.; Giniger, R.; Miller, Y.; Gerber, R. B.; Cheshnovsky, O., "Critical Size for Intracluster Proton Transfer from Water to an Anion," Angew. Chem. Int. Ed., 2008, DOI: 10.1002/anie.200800542

Cramer and Truhlar¹ have published a nice review of their SM8 approach to evaluated solvation energy. Besides a quick summary of the theoretical approach behind the model, they detail a few applications. Principle among these is (a) the very strong performance of SM8 relative to some of the standard approaches in the major QM codes (see my previous blog post), (b) modeling interfaces, and (c) computing pK_a values of organic compounds.

References

(1) Cramer, C. J.; Truhlar, D. G., "A Universal Approach to Solvation Modeling," Acc. Chem. Res. 2008, 41, 760-768, DOI: 10.1021/ar800019z.

Bickelhaupt has reported a broad benchmark study of the prototype S_N2 and E2 reactions.¹ These are the reactions of ethyl fluoride with fluoride and ethyl chloride with chloride (Scheme A). The critical points were optimized at OLYP/TZ2P and then CCSD(T)/CBS energies are used as benchmark. A variety of different density functionals were then used to obtain single-point energies.

Scheme A

The relative energies of the transition states for the six different reactions are listed for some of the functionals in Table 1. (These are energies relative to separated reactants – and keep in mind that an ion dipole complex is formed between the reactants and the transition states – Bickelhaupt calls this a “reaction complex”.)

Table 1. Relative energies (kcal mol^-1) of the transition states for the six reactions shown in Scheme A.

There is a lot more data in this paper, along with a summary of the mean absolute errors in the overall and central barriers that mimics the data I show in Table 1. The trends are pretty clear. Generalized gradient approximation (GGA) functions – like BLYP, PW91, and PBE – dramatically underestimate the barriers. The hybrid functionals perform much better. The recently maligned B3LYP functional gets the correct trend and provides reasonable estimates of the barriers. Truhlar’s MO5-2X and MO6-2X functionals do very well in matching up the barrier heights along with getting the correct trends in the relative barriers. Simply looking for the functional with the lowest absolute error is not sufficient; BHandH and MO6-L have small errors but give a wrong trend in barriers, predicting that the S_N2 reaction is preferred over the E2 for the fluoride reaction.

Reference

(1) Bento, A. P.; Sola, M.; Bickelhaupt, F. M., "E2 and S_N2 Reactions of X^- + CH₃CH₂X (X = F, Cl); an ab Initio and DFT Benchmark Study," J. Chem. Theory Comput., 2008, 4, 929-940, DOI: 10.1021/ct700318e.

Schleyer continues his study of aromaticity with a paper¹ that picks up on the theme presented in one² I have previously blogged on – the relationship between a formally aromatic pyrazine and formally antiaromatic dihydropyrazine. He now examines the diazotetracene 1 and it dihydro analogue 2.¹ In terms of formal electron count, 1 should be aromatic, just like the all carbon analogue tetracene 3, and 2 should be antiaromatic.

Schleyer used the NICS_πzz values obtained in the center of each ring to evaluate the aromatic/antiaromatic character of these three molecules. These calculations were performed using canonical molecular orbitals and repeated using localized molecular orbitals. The results are similar for each method, and the canonical MO values are presented in Table 1. As expected for an aromatic compound, each ring of tetracene 3 has large negative NICS values, indicating that each ring is locally aromatic and the molecule as a whole is aromatic. The same is true for the diazotetracene 1. (In fact the NICS values for 1 and 3 are remarkably similar.) However, for 2, the dihydropyrazine ring has a positive NICS values, indicative of a locally antiaromatic ring. While the three phenyl rings have negative NICS values, these absolute values are smaller than for the rings of 1 or 3, indicating an attenuation of their aromaticity. Nonetheless, the sum of the NICS values of 2 is negative, suggesting that the molecule is globally aromatic, though only marginally so. This is due to the antiaromaticity of the dihydropyrazine ring being delocalized to some extent over the entire molecule. Schleyer, concludes that “large 4n π compounds […] are not appreciably destabilized relative to their 4n+2 π congeners.”

Table 1 NICS_πzz (ppm) for each ring of 1-3 and their sum.¹

References

(1) Miao, S.; Brombosz, S. M.; Schleyer, P. v. R.; Wu, J. I.; Barlow, S.; Marder, S. R.; Hardcastle, K. I.; Bunz, U. H. F., "Are N,N-Dihydrodiazatetracene Derivatives Antiaromatic?," J. Am. Chem. Soc., 2008, 130, 7339-7344, DOI: 10.1021/ja077614p.

(2) Miao, S.; Schleyer, P. v. R.; Wu, J. I.; Hardcastle, K. I.; Bunz, U. H. F., "A Thiadiazole-Fused N,N-Dihydroquinoxaline: Antiaromatic but Isolable," Org. Lett. 2007, 9, 1073-1076, DOI: 10.1021/ol070013i

InChIs

1: InChI=1/C18H12/c1-2-6-14-10-18-12-16-8-4-3-7-15(16)11-17(18)9-13(14)5-1/h1-12H

2: InChI=1/C16H10N2/c1-2-6-12-10-16-15(9-11(12)5-1)17-13-7-3-4-8-14(13)18-16/h1-10H

3: InChI=1/C16H12N2/c1-2-6-12-10-16-15(9-11(12)5-1)17-13-7-3-4-8-14(13)18-16/h1-10,17-18H