Wednesday, July 25, 2012

Aromatic Transition States in Nonpericyclic Reactions: Anionic 5-Endo Cyclizations Are Aborted Sigmatropic Shifts

Gilmore, K.; Manoharan, M.; Wu, J. I. C.; Schleyer, P. v. R.; Alabugin, I. V. J. Am. Chem. Soc.2012, 134, 10584–10594 (Paywall)
Contributed by Steven Bachrach.
Reposted from Computational Organic Chemistry with permission

The activation energy for the 5-endo-dig reaction of the anion 1 is anomalously low compared to its 4-endo-dig and 6-endo-dig analogues. Furthermore, the TS is quite early, earlier than might be expected based on the Hammond Postulate. Alabugin and Schleyer have examined this reaction and found some interesting results.1
First, NICS(0) values for a series of related intermolecular anionic attack at alkynes show some interesting trends (Table 1). Two of the transition states look like they might be aromatic: the TSs for the 3-exo-dig and the 5-endo-dig reaction have NICS(0) values that are quite negative. However, given the geometry of these TSs, particularly the close proximity of the σ bonds to the ring center, one might be concerned about contamination of these orbitals. So, NICS(0)MOzz computations, which look at the tensor component perpendicular to the ring using just the π-MOs, shows that the 3-exo-dig is likely non-aromatic (NICS(0)MOzz is near zero), the TS for the 4-endo-dig reaction is antiaromatic (NICS(0)MOzz very positive) and the TS for the 5-endo-dig reaction is aromatic (NICS(0)MOzz is very negative. So this last reaction is the first example of an aromatic transition that is not for a pericyclic reaction!

Table 1. NICS(0) and NICS(0)MOzz for the TS of some anionic alkyne cyclizations.




5-endo-dig (1)
These authors argue that the reaction of 1 is an “aborted” sigmatropic shift. A normal pericyclic reaction is a single step with a single (concerted) transition state. An interrupted sigmatropic shift has an intermediate that lies higher in energy than the reactants, such as in the Bergman cyclization of an enediyne. The aborted sigmatropic shift has an intermediate that lies lower in energy than the reactants, such as in the cyclization of 1.


(1) Gilmore, K.; Manoharan, M.; Wu, J. I. C.; Schleyer, P. v. R.; Alabugin, I. V. "Aromatic Transition States in Nonpericyclic Reactions: Anionic 5-Endo Cyclizations Are Aborted Sigmatropic Shifts," J. Am. Chem. Soc.2012134, 10584–10594, DOI: 10.1021/ja303341b

Saturday, July 21, 2012

Chemical Networks (Triple Header!)

A back-to-back-to-back (!) set of three papers in Angewandte Chemie from Bartosz Grzybowski and co-workers. All three articles concern the development of Chemical Networks and their application in synthetic chemistry, of which more later. It is often said that the realm of synthesis is both art and science, however, the wealth of empirical observations made over centuries of making molecules underpin the field. As Grzybowski remarks here, “it is simply beyond cognition of any individual human to understand and analyze all this collective chemical knowledge”, and most chemists already search online synthesis databases to perform individual steps, but perhaps the role of automated computational synthetic route selection, and reaction design is set to grow? Also see Dean Tantillo's recent post on CCH.

Grzybowksi’s group has constructed a network of organic chemistry (NOC) from reactions in the chemical literature since 1779 until present day: reactants and products are represented by nodes in this graph and known chemical interconversions by edges. From this NOC containing seven million reactions, the first paper of the series seeks to discover new ways of performing consecutive reactions in the same vessel (so-called “one pot” reactions). From known reactions that interconvert A to B and B to C, the authors have coded filters that check for compatability between solvents, reagents, catalysts etc so that the two steps may be performed in the same reaction vessel, thus creating a novel way to prepare C from A in one step. Typically synthetic organic protocols are the result of much tinkering and optimization studies in the lab: in contrast the NOC predictions have yield a number of two, three and four step one-pot reactions that give moderate to good yields without any human optimization.
In the second paper the group turn their attention to designing “optimal” reaction pathways to synthesise a given target molecule. Again the NOC is used, this time to propagate backwards from the target via an initial synthetic plan to starting materials. A Metropolis Monte Carlo algorithm is used to randomly sample alternative routes in order to minimize a penalty function associated with the cost of performing each step. Impressively this approach has been used already by a synthesis company to reduce their costs. Additional costs such as waste disposal or energy costs associated with heating/cooling are undoubtedly important for chemistry on the process scale, and perhaps these could be incorporated in future implementations of the optimization.
The third application of a chemical network considers the synthesis of chemical warfare agents. Reaction networks are explored starting from commonly available household chemicals. Thankfully the paper is careful not to disclose any of the synthetic steps involved, and the authors propose strengthening existing regulation of substances by not only regulating single molecules but also combinations of reagents that have been ranked according to game theory as more likely to be used. 

Friday, July 20, 2012

A Paramagnetic Bonding Mechanism for Diatomics in Strong Magnetic Fields

Kai K. Lange, E. I. Tellgren, M. R. Hoffmann and T. Helgaker Science 2012, 337, 327 (Paywall)

A new bonding mechanism
As chemists we are familiar with two types of strong bonds occurring between atoms, covalent and ionic. This paper shows that when very strong magnetic fields (of the order of 105 T) are applied, a third bonding mechanism arrises. Helgaker and co-workers term this perpendicular paramagnetic bonding.

Binding triplet H2
Whilst previous Hartree-Fock calculations have shown that the lowest triplet state of H2 becomes bound in strong magnetic fields, this investigation uses the recently developed LONDON code to demonstrate the same phenomena at the Full-CI level. Similar calculations (again, with a very strong magnetic field) on the triplet state of He2 show a considerable strengthening of the interaction between the constituent atoms.

The nature of this bonding
By examining the behaviour of the molecular orbitals under different orientations relative to the external magnetic field, the authors note a stabilisation of antibonding orbitals in the perpendicular orientation, leading to a new type of bonding interaction. Although the potential of a new chemical bonding mechanism is undoubtably exciting, the magnetic fields required are beyond those that can be currently generated in a lab. However, such fields are present on some stellar objects and the findings of this paper are likely to aid in the spectroscopy of such bodies.

Thursday, July 5, 2012

Dynamic Origin of the Stereoselectivity of a Nucleophilic Substitution Reaction

Bogle, X. S.; Singleton, D. A. Org. Lett., 2012, 14, 2528-2531 (Paywall)
Contributed by Steven Bachrach.
Reposted from Computational Organic Chemistry with permission

I think most organic chemists hold dear to their hearts the notion that selectivity is due to crossing over different transition states. Readers of my book and this blog know of the many examples where this notion simply is not true (see here). This post discusses yet another example taking place in a seemingly simple reaction.

Singleton has examined the nucleophilic substitution reaction of 1 with sodium tolylsulfide.1 The mono substitution gives potentially two different stereoproducts 2 and 3. The experimental ratio of these products 2:3 is 81:19. (Note that things are a bit more complicated because disubstitution can also occur, but this has been factored into the product ratio.)
Based on previous literature, this reaction is likely to proceed in a concerted fashion, and so one might anticipate running computations to locate a transition state leading to 2 and a transition state leading to3. In fact, Singleton finds six different TSs (the lowest energy TS 4 is shown in Figure 1), all within 2 kcal mol-1 of each other at PCM(ethanol)/B3LYP/6-31+G**. However, the intrinsic reaction coordinate going forward from each of these six TSs leads solely to 2; no TS could be located that connects to 3! (Computations were also performed at PCM(ethanol)/M06-2x/6-31+G** which give very similar results.) Classical transition state theory would lead one to conclude that only 2 should be formed, inconsistent with experiment.


Figure 1. PCM/B3LYP/6-31+G** optimized structures of TSs 4 and 5.

Furthermore, no intermediate could be located. This is consistent with a concerted mechanism. A second transition state was located which interconverts 2 and 3 with the involvement of a chloride – a sort of addition/rotation/elimination process. This TS 5 is also shown in Figure 1.

A direct dynamics study was performed, and 197 trajectories were computed. Of these, 185 trajectories went to product: 156 to 2 and 29 to 3, for a ratio of 84:16 – in amazing agreement with experiment! The product selectivity is due entirely to dynamic effects. In fact, it is one vibrational mode that dictates the product distribution. Essentially, the nature of the rotation about the C=C bond differentiates the eventual route, with a clockwise rotation leading always to 2 and a counterclockwise rotation leading about a third of the time to 3.


(1) Bogle, X. S.; Singleton, D. A. "Dynamic Origin of the Stereoselectivity of a Nucleophilic Substitution Reaction," Org. Lett.201214, 2528-2531, DOI: 10.1021/ol300817a.

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