All Five Forms of Cytosine Revealed in the Gas Phase

Alonso, J. L.; Vaquero, V.; Peña, I.; López, J. C.; Mata, S.; Caminati, W.  Angew. Chem. Int. Ed. 2013, 52, 2331-2334
Contributed by Steven Bachrach.
Reposted from Computational Organic Chemistry with permission

Alonso and coworkers have again (see this post employed laser-ablation molecular-beam Fourier-transform microwave (LA-MB-MW)spectroscopy to discern the gas phase structure of an important biological compound: cytosine.¹ They identified five tautomers of cytosine 1-5. Comparison between the experimental and computational (MP2/6-311++G(d,p) microwave rotational constants and nitrogen nuclear quadrupole coupling constants led to the complete assignment of the spectra. The experimental and calculated rotational constants are listed in Table 1.

Table 1. Rotational constants (MHz) for 1-5.

	1		2		3		4		5
	Expt	calc	Expt	calc	Expt	calc	Expt	calc	Expt	calc
A	3951.85	3934.5	3889.46	3876.5	3871.55	3856.0	3848.18	3820.1	3861.30	3844.2
B	2008.96	1999.1	2026.32	2014.7	2024.98	2012.3	2026.31	2019.0	2011.41	1999.7
C	1332.47	1326.8	1332.87	1326.9	1330.34	1323.3	1327.99	1324.0	1323.20	1318.4

The experimental and computed relative free energies are listed in Table 2. There is both not a complete match of the relative energetic ordering of the tautomers, nor is there good agreement in their magnitude. Previous computations² at CCSD(T)/cc-pVQZ//CCSD//cc-pVTZ are in somewhat better agreement with the gas-phase experiments.

Table 2. Relative free energies (kcal mol^-1) of 1-5.

	expt	MP2/ 6-311++G(d,p)	CCSD(T)/cc-pVQZ// CCSD//cc-pVTZ
1	0.0	0.0	0.0
2	0.47	0.70	0.7
3	0.11	1.19	0.2
4	0.83	3.61	0.7
5		5.22

References

(1) Alonso, J. L.; Vaquero, V.; Peña, I.; López, J. C.; Mata, S.; Caminati, W. "All Five Forms of Cytosine Revealed in the Gas Phase," Angew. Chem. Int. Ed. 2013, 52, 2331-2334, DOI:10.1002/anie.201207744.

(2) Bazso, G.; Tarczay, G.; Fogarasi, G.; Szalay, P. G. "Tautomers of cytosine and their excited electronic states: a matrix isolation spectroscopic and quantum chemical study," Phys. Chem. Chem. Phys., 2011,13, 6799-6807, DOI:10.1039/C0CP02354J.

InChIs

cytosine: InChI=1S/C4H5N3O/c5-3-1-2-6-4(8)7-3/h1-2H,(H3,5,6,7,8)
InChIKey=OPTASPLRGRRNAP-UHFFFAOYSA-N

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Three- and four-body corrected fragment molecular orbital calculations with a novel subdividing fragmentation method applicable to structure-based drug design

Chiduru Watanabe, Kaori Fukuzawa, Yoshio Okiyama, Takayuki Tsukamoto, Akifumi Kato, Shigenori Tanaka, Yuji Mochizuki, and Tatsuya Nakano Journal of Molecular Graphics and Modelling 2013, 41, 31.
Contributed by +Jan Jensen


One of the advantages of fragmentation based electronic structure methods over conventional linear scaling method is that one gets an automatic energy analysis in terms of interfragment interaction energies (IFIEs).  When applied to protein-ligans interactions such IFIE analyses can aid in the drug design process.  

However, in order to obtain accurate results the whole ligand is often treated as one fragment and the contribution of individual ligand functional groups to the binding is lost.  A main reason that accuracy depends on fragment size is that as fragments get smaller, many-body short-range interaction energies such as exchange repulsion become important.  Most fragmentation methods only treat such effects at the two-body level, while the Fragment Molecular Orbital (FMO) method also has a three-body corrected version (FMO3).  Nakano et al. have recently developed a four-body version of the FMO4 which yields accurate total energies for functional group-sized fragments, and this study by Watanabe et al presents the corresponding IFIE analysis.

At the MP2/6-31G level of theory and using an FMO2 calculation using one residue per monomer as a reference, the accuracy and CPU cost is comparable to an FMO3 calculation if the fragment size is roughly halved.  The CPU increases only by a factor of three on going to FMO4, while the accuracy is increased by an order of magnitude.

The relatively modest increase in CPU time is due to the fact that the many-body short-range corrections only are computed for fragments in close proximity to one another. Thus, the number of corresponding trimer and tetramer calculations scale roughly linearly with system size.  I have explored the question of computational efficiency and fragment-size further in this post.


 
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The Melatonin Conformer Space: Benchmark and Assessment of Wave Function and DFT Methods for a Paradigmatic Biological and Pharmacological Molecule

Fogueri, U. R.; Kozuch, S.; Karton, A.; Martin, J. M. L. J. Phys. Chem. A 2013, 117, 2269
Contributed by Steven Bachrach.
Reposted from Computational Organic Chemistry with permission

Conformational analysis is one of the tasks that computation chemistry is typically quite adept at and computational chemistry is frequently employed for this purpose. Thus, benchmarking methods for their ability to predict accurate conformation energies is quite important. Martin has done this for alkanes¹(see this post), and now he has looked at a molecule that contains weak intermolecular hydrogen bonds. He examined 52 conformations of melatonin 1.² The structures of the two lowest energy conformations are shown in Figure 1.

1

1a

1b

Figure 1. Structures of the two lowest energy conformers of 1 at SCS-MP2/cc-pVTZ.

The benchmark (i.e. accurate) relative energies of these conformers were obtained at MP2-F12/cc-pVTZ-F12 with a correction for the role of triples: (ECCSD(T)/cc-pVTZ)-E(MP2/cc-pVTZ)). The energies of the conformers were computed with a broad variety of basis sets and quantum methodologies. The root mean square deviation from the benchmark energies is used as a measure of the utility of these alternate methodologies. Of particular note is that HF predicts the wrong ordering of the two lowest energy isomers, as do some DFT methods that use small basis sets and do not incorporate dispersion.

In fact, other than the M06 family or double hybrid functionals, all of the functionals examined here (PBE. BLYP, PBE0, B3LYP, TPSS0 and TPSS) have RMSD values greater than 1 kcal mol^-1. However, inclusion of a dispersion correction, Grimme’s D2 or D3 variety or the Vydrov-van Voorhis (VV10) non-local correction (see this post for a review of dispersion corrections), reduces the error substantially. Among the best performing functionals are B2GP-PLYP-D3, TPSS0-D3, DSD-BLYP and M06-2x. They also find the MP2.5 method to be a practical ab initio alternative. One decidedly unfortunate result is that large basis sets are needed; DZ basis sets are simply unacceptable, and truly accurate performance requires a QZ basis set.

References

(1) Gruzman, D.; Karton, A.; Martin, J. M. L. "Performance of Ab Initio and Density Functional Methods for Conformational Equilibria of CnH2n+2 Alkane Isomers (n = 4-8)," J. Phys. Chem. A 2009, 113, 11974–11983, DOI: 10.1021/jp903640h.

(2) Fogueri, U. R.; Kozuch, S.; Karton, A.; Martin, J. M. L. "The Melatonin Conformer Space: Benchmark and Assessment of Wave Function and DFT Methods for a Paradigmatic Biological and
Pharmacological Molecule," J. Phys. Chem. A 2013, 117, 2269-2277, DOI: 10.1021/jp312644t.

InChIs

1: InChI=1S/C13H16N2O2/c1-9(16)14-6-5-10-8-15-13-4-3-11(17-2)7-12(10)13/h3-4,7-8,15H,5-6H2,1-2H3,(H,14,16)
InChIKey=DRLFMBDRBRZALE-UHFFFAOYSA-N

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Zwitterions and Unobserved Intermediates in Organocatalytic Diels–Alder Reactions of Linear and Cross-Conjugated Trienamines

Dieckmann, A.; Breugst, M.; Houk, K. N.  J. Am. Chem. Soc. 2013, 135, 3237-3242
Contributed by Steven Bachrach.
Reposted from Computational Organic Chemistry with permission

Halskov, et al.¹ reported the interesting Diels-Alder selectivity shown in Scheme 1. The linear trienamine1 did not undergo the Diels-Alder addition, while the less stable cross-conjugated diene 2 does react with 3 with high diastereo- and enantioselectivity. Their MPW1K/6-31+G(d,p) computations on a model system, carried out for a gas-phase environment, indicated a concerted mechanism, with thermodynamic control. However, the barrier for the reverse reaction for the kinetic product was computed to be greater than 30 kcal mol^-1, casting doubt on the possibility of thermodynamic control.

Scheme 1.

Houk and co-workers² have re-examined this reaction with the critical addition of performing the computation including the solvent effects. Since the stepwise alternatives involve the formation of zwitterions, solvent can be critical in stabilizing these charge-separated species, intermediates that might be unstable in the gas phase. Henry Rzepa has pointed out in his blog and on many comments in this blog about the need to include solvent, and this case is a prime example of the problems inherent in neglecting solvation.

Using models of the above reaction Houk located two zwitterionic intermediates of the Michael addition for both the reactions of 4 with 6 and of 5 with 6. The second step then involves the closure of the ring to give what would be Diels-Alder products. This is shown in Scheme 2. They were unable to locate transition states for any concerted pathways. The computations were done at M06-2x/def2-TZVPP/IEFPCM//B97D/6-31+G(d,p)/IEFPCM, modeling trichloromethane as the solvent.

Scheme 2. Numbers in italics are energies relative to 4 + 6.

The activation barrier for the second step in each reaction is very small, typically less than 5 kcal mol^-1, so the first step is rate determining. The lowest barrier is for the reaction of 5 leading to 9, analogous to the observed product. Furthermore, 9 is also the thermodynamic product. Thus, the regioselectivity is both kinetically and thermodynamically controlled through a stepwise reaction. This conclusion is only possible by including solvent in order to stabilize the zwitterionic intermediates, and should be a word of caution for everyone doing computations: be sure to include solvent for any reactions that involved charged or charge-separated species at any point along the reaction pathway!

References

(1) Halskov, K. S.; Johansen, T. K.; Davis, R. L.; Steurer, M.; Jensen, F.; Jørgensen, K. A. "Cross-trienamines in Asymmetric Organocatalysis," J. Am. Chem. Soc. 2012, 134, 12943-12946,
DOI: 10.1021/ja3068269.

(2) Dieckmann, A.; Breugst, M.; Houk, K. N. "Zwitterions and Unobserved Intermediates in Organocatalytic Diels–Alder Reactions of Linear and Cross-Conjugated Trienamines," J. Am. Chem. Soc. 2013, 135, 3237-3242, DOI: 10.1021/ja312043g.

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