Archive for October, 2011

Substitution vs. addition: dynamic effects

Reactions whose outcomes depend on dynamic processes is a major theme of my book and this blog. The recent study of the reaction of a nucleophile (hydroxide) with bromoacetophenones adds yet another case for post-transition state product determination.

Itoh and Yamataka have examined the reaction of hydroxide with substitutes α-bromoacetophenones 1.1 The nucleophile can attack at the carbonyl carbon or the α-carbon, though both lead ultimately to the same product, as shown in Scheme 1.

Scheme 1

B3LYP/6-31+G* computations of the reaction surface with a variety of different substituents on the phenyl ring of 1 located in all cases a single transition state for the two different reactions (addition and substitution). This TS is shown in Figure 1 for the parent case (X=H).

Figure 1. The single transition state for the addition and substitution reaction of 1 and hydroxide.

Tracing the IRC forward leads to either the carbonyl addition product or the substitution product, and which path is traced depends to some extent on the nature of the substituent. Most intriguing is that trajectories initiated at the transition state lead to both products. So once again, we see a case where a single transition state leads to two products, and product selectivity is determine by the dynamics – the initial conditions at the TS dictate which of the two products is eventually obtained.


(1) Itoh, S.; Yoshimura, N.; Sato, M.; Yamataka, H., "Computational Study on the Reaction Pathway of α-Bromoacetophenones with Hydroxide Ion: Possible Path Bifurcation in the Addition/Substitution Mechanism," J. Org. Chem., 2011, 70, 8294–8299, DOI: 10.1021/jo201485y

Dynamics &Substitution Steven Bachrach 24 Oct 2011 13 Comments

[6]Saddlequat – the ruber glove inversion

In 1955 Mislow1 discussed the possibility of enatiomers interchanging via a path that was entirely chiral, never passing through an achiral structure. His analogy is the inversion of a rubber glove, taking a right hand rubber glove and pulling it inside out creates a left hand glove (its mirror image) but never passing through an achiral glove. Well, now a helicene with this type of stereochemistry has been developed, with a stable chiral intermediate.2

Helicenes typically interchange (PMP) through an achiral saddle-like structure. But larger helicenes can have high-lying intermediates along this pathway. Helquat P-1 interchanges to M-1 through the intermediate 2, which is an achiral structure and can be isolated.

Computations at B3LYP/def2-TZVP//PBE/def2-SV(P) with dispersion corrections (and PCM simulating DMSO) of the inversion process identified a number of intermediates and transition states along the stereoinversion pathway. The intermediate 2 lies 18.4 kJ mol-1 above 1. These structures are shown in Figure 1. The highest lying TS between 2 and P-1 (labeled TSP in Figure 1) is 119 kJ mol-1 above 2. The highest lying TS on the path from 2 to M-1 (labeled TSM in Figure 1) is 138 kJ mol-1 above 2. Note that going from 2 to P-1 is not the mirror image path of going from 2 to M-1.






Figure 1. Optimized structures of 1, 2, and the highest transition states interconverting them.

Heating racemic 2 and following the conversion to 1 with NMR gives the activation barrier of 119 kJ mol-1, in excellent agreement with the computation.

Racemic 2 was resolved through differential crystallization and its x-ray structure indicates it is (+)-[Sa,Ra]. Heating it does give just P-1, as predicted by the computations. Then heating P-1 to 180 °C does racemize it, with an experimental barrier of 157.7 kJ mol-1. The computations predict a barrier of 156.6 kJ mol-1, again in fine agreement with experiment. Overall, a nice piece showing experiment and computation working together to provide an understanding of an interesting chemical system!


(1) Mislow, K.; Bolstad, R., "Molecular Dissymmetry and Optical Inactivity," J. Am. Chem. Soc., 1955, 77, 6712-6713, DOI: 10.1021/ja01629a131

(2) Adriaenssens, L.; Severa, L.; Koval, D.; Cisarova, I.; Belmonte, M. M.; Escudero-Adan, E. C.; Novotna, P.; Sazelova, P.; Vavra, J.; Pohl, R.; Saman, D.; Urbanova, M.; Kasicka, V.; Teply, F., "[6]Saddlequat: a [6]helquat captured on its racemization pathway," Chem. Sci. 2011, ASAP, DOI: 10.1039/C1SC00468A


1: InChI=1/C27H26N2/c1-2-11-23-20(8-1)15-19-29-18-7-10-22-14-13-21-9-3-5-16-28-17-6-4-12-24(28)25(21)26(22)27(23)29/h1-2,4,6,8,11-15,17,19H,3,5,7,9-10,16,18H2/q+2

Stereochemistry Steven Bachrach 18 Oct 2011 2 Comments

Acene Dimerization

Bendikov and co-workers have examined the dimerization of linear acenes at M06-2x/6-31G(d).1 They have looked at the formal forbidden [4+4] reaction that takes, for example, 2 molecules of benzene into three possible dimer products 1Panti1-2, 1Psyn1-2, and 1Psyn1-4. The relative energies of these products increases in that order, and all three are much higher in energy than reactants; the lowest energy dimer is 1Panti1-2, lying 47.4 kcal mol-1 above two benzene molecules. Similarly, the dimerization of naphthalene is also endothermic, but the formation of the symmetric dimer of anthracene 3P-2,2’ is exothermic by 5.4 kcal mol-1. This gibes nicely with the best estimate of -9 ± 3 kcal mol-1.2 Dimerization of the higher acenes are increasingly exothermic.

The transition state for the dimerization of benzene is concerted, though very asymmetric, as seen in Figure 1. Its energy is quite high (77.79 kcal mol-1) and so this reaction can be completely discounted. The TS for the dimerization of naphthalene is also concerted and asymmetric, but the reaction pathway for the dimerization is stepwise, with a diradical intermediate. Furthermore, the highest barrier for this stepwise reaction is 33.3 kcal mol-1. The activation energy of the back reaction (anthracene dimer to two anthrecene molecules) was measured 36.3 kcal mol-1,3 and the computed barrier of 38.7 kcal mol-1 is in nice agreement. The computed barriers for the dimerization of the higher acenes are predicted to be even lower than that of anthracene, consistent with the observation of dimers of these molecules.





Figure 1. M06-2x /6-31G(d) optimized structures.

I was curious that the authors did not consider the formally allowed [4+2] dimerization, leading for example to 1P-42. So, I optimized this product and the concerted transition state leading to it. These are shown in Figure 1. The barrier through this transition state is still very large (54.1 kcal mol-1) but it is 23 kcal mol-1 lower in energy than the barrier of the [4+4] reaction! The Product of the [4+2] is also lower in energy (by 9 kcal mol-1) than 1Panti1-2. It seems to me that this type of dimerization is worth examining too – though I must say I have not as yet looked to see if anyone has explored this already.


(1) Zade, S. S.; Zamoshchik, N.; Reddy, A. R.; Fridman-Marueli, G.; Sheberla, D.; Bendikov,
M., "Products and Mechanism of Acene Dimerization. A Computational Study," J. Am. Chem. Soc., 2011, 133, 10803-10816, DOI: 10.1021/ja106594v

(2) Grimme, S.; Diedrich, C.; Korth, M., "The Importance of Inter- and Intramolecular van der Waals Interactions in Organic Reactions: the Dimerization of Anthracene Revisited," Angew. Chem. Int. Ed., 2006, 45, 625-629, DOI: 10.1002/anie.200502440

(3) Greene, F. D., "Problems of stereochemistry in photochemical reactions in the anthracene area," Bull. Soc. Chim. Fr., 1960, 1356-1360


Benzene: InChI=1/C6H6/c1-2-4-6-5-3-1/h1-6H

1Panti1-2: InChI=1/C12H12/c1-2-6-10-9(5-1)11-7-3-4-8-12(10)11/h1-12H

1Psyn1-2: InChI=1/C12H12/c1-2-6-10-9(5-1)11-7-3-4-8-12(10)11/h1-12H

1Psyn1-4: InChI=1/C12H12/c1-2-10-4-3-9(1)11-5-7-12(10)8-6-11/h1-12H

1P-42: InChI=1/C12H12/c1-2-4-12-10-7-5-9(6-8-10)11(12)3-1/h1-12H

Anthracene: InChI=1/C14H10/c1-2-6-12-10-14-8-4-3-7-13(14)9-11(12)5-1/h1-10H

3P-2,2’: InChI=1/C28H20/c1-2-10-18-17(9-1)25-19-11-3-4-12-20(19)26(18)28-23-15-7-5-13-21(23)27(25)22-14-6-8-16-24(22)28/h1-16,25-28H

Aromaticity &Diels-Alder &electrocyclization Steven Bachrach 11 Oct 2011 1 Comment

Structure of 1-aminocyclopropylcarboxylic acid

There are three generic conformations of α-amino acids in the gas phase: A-C. These are stabilized by intramolecular hydrogen bonds. While computations suggest that all three are close in energy, the very detailed laser ablation- molecular beam-Fourier transform microwave (LA-MB-FTMW) experiments of the Alonso group (mentioned in these previous posts: guanine, cysteine, ephedrine) have identified only the first two conformations. Cooling of the structures in the jet expansion appears to be the reason for the loss of the (slightly) higher energy conformer C.

Alonso now reports on the structure of 1-aminocyclopropanecarboxylic acid 1.1 The three MP2/6-311+G(d,p) optimized conformation are shown in Figure 1. The interaction between the cyclopropyl orbitals and the carbonyl π-bond suggests that only two structures (where the carbonyl bisects thecyclopropyl plane) will exist and that rotation between them may require passage through a prohibitively high barrier. In fact, computations suggest a barrier of 2000 cm-1 (5.7 kcal mol-1). This is much larger than the typical rotation barrier of the amino acids that interconvert A with C, which are about 400 cm-1 (1 kcal mol-1).




After careful examination of the microwave spectrum, all three conformations 1A-C were identified by comparing the experimental value of the rotational constants, and 14N nuclearquadrupole coupling constants with the computed values. Really excellent agreement is found, including in the ratio of the relative amounts of the three isomers. Once again, we have an exquisite example of the importance of computations and experiments being used in conjunction to solve interesting chemical problems.


(1) Jimenez, A. I.; Vaquero, V.; Cabezas, C.; Lopez, J. C.; Cativiela, C.; Alonso, J. L., "The Singular Gas-Phase Structure of 1-Aminocyclopropanecarboxylic Acid (Ac3c)," J. Am. Chem. Soc., 2011, 133, 10621-10628, DOI: 10.1021/ja2033603


1: InChI=1/C4H7NO2/c5-4(1-2-4)3(6)7/h1-2,5H2,(H,6,7)/f/h6H

amino acids Steven Bachrach 04 Oct 2011 No Comments