Nitroso know-how

Computational chemistry provides new insight into the mechanism of stereochemical control in the nitroso ene reaction. Jeremy Harvey reports

Nitric oxide (NO) was Science magazine’s ’molecule of the year’ in 1992, following the discovery of its signalling role in biology. This discovery was also rewarded with the 1998 Nobel prize in physiology or medicine. Despite this, NO’s close cousins, nitroso compounds R-NO, some of which are involved in the transport of NO around the body, occupy a relatively obscure corner of organic chemistry - many chemistry undergraduates would probably be hard pressed to remember anything about them.

Yet the nitroso group undergoes some important organic reactions: Diels-Alder cycloaddition to dienes is a useful way of forming new carbon-nitrogen bonds, and gives high diastereoselectivities when carried out with chiral nitroso species. Reacting nitroso compounds with alkenes bearing C-H bonds adjacent to the double bond leads to allylic hydroxylamines. However, until the recent mechanistic studies Waldemar Adam and coworkers at the University of W?rzburg, Germany, this nitroso ene reaction had attracted little interest.

Trying to understand reaction mechanisms in detail is not just of academic interest. For example, to design efficient asymmetric syntheses of pharmaceutical compounds based on the nitroso ene reaction, it would be useful to be able to answer questions such as: What is the rate-limiting step? What is the structure of the key transition state(s)? How do substituents affect this? How efficiently will a given chiral group discriminate between diastereoisomeric transition states? The new experiments mentioned above go a long way to answering some of these questions, but theory can be useful too.

The celebrated Woodward-Hoffmann rules make very clear predictions: the ene reaction and Diels-Alder cycloaddition are both examples of pericyclic reactions (ie they can be written as occurring in a single step via cyclic transition states in which all the bond-forming and breaking takes place simultaneously), for which the rules predict that such a concerted mechanism should be favoured.

More detailed theory uses the basic laws of quantum mechanics, and powerful computers, to address chemical reaction mechanisms, and this approach is increasingly recognised as a valuable complement to experiment. In a paper in Organic and Biomolecular Chemistry, Kendall Houk and his postdoc Andrew Leach at the University of California in Los Angeles, have recently demonstrated the vital contribution that computations can make to understanding pericyclic reaction mechanisms, and in particular the nitroso ene reaction.

Some years ago, computational studies were notorious for providing inaccurate insight into the electronic structure of ’model’ compounds derived from the experimental systems by stripping away all the interesting substituents. In their study, Houk and Leach do start by studying such a ’model’ reaction, that of nitrous acid (HNO) with propene. However, they use state-of-the-art coupled-cluster and multi-reference perturbation methods as well as the reasonably accurate but less time-consuming density functional theory (DFT). Given the good agreement between these different approaches, they then apply DFT alone to larger systems, including the ’real’ reaction, that of p-nitro-nitrosobenzene with alkenes.

Leach and Houk’s mechanism for the ene reaction between HNO and propene Org. Biomol. Chem., 2003, 1, 1389

What do they learn? Their main conclusion is that the reaction takes place in a stepwise manner: initial addition of the nitroso compound to the alkene occurs to give a diradical intermediate (2) with a new C-N bond, which then undergoes intramolecular hydrogen atom transfer from carbon to oxygen to give the product (4). Before this, the diradical can also undergo reversible cyclisation to give a three-membered ring intermediate, an aziridine N-oxide (6). The calculated energy barriers for these steps all lie close in energy. The authors were unable to find a Woodward-Hoffmann-like concerted transition state, confirming that in this case such a pathway would be unfavourably high in energy.

Leach and Houk show that this mechanism is consistent with one of the most stringent tests provided by experiment: kinetic isotope effects (KIEs), or the difference in reactivity between substrates with hydrogen atoms only, and others where hydrogen is replaced by deuterium. In the mechanism mentioned above the second, hydrogen atom transfer, step is expected to give a fairly large KIE, whereas the initial addition step is not. Depending on the reactants, the observed KIEs vary between the two extremes, which the authors show can only occur if, as they have calculated, the two steps involve barriers of very similar height.

Diradical intermediates are traditionally associated with loss of stereochemical integrity, due to rotation around single bonds. In the nitroso ene reactions considered, a mechanism in which such rotations occurred would still lead to the same products, but some of the KIEs would be different. The prediction that rotation around single bonds therefore do not occur in the nitroso ene reaction is puzzling at first, but can be explained by introducing a refinement: the diradicals involved are polarised, with some zwitterionic ^-O-N-C-C⁺  character and a weak O???H hydrogen bond. This makes the calculated barrier heights for rotation around single bonds slightly higher than expected - and higher than the (low-lying) barriers for further reaction by hydrogen atom transfer. Biradicals can be more complicated than previously thought.

This study gives much food for thought to chemists planning to use nitroso ene reactions. As a result maybe nitroso compounds will gain a more prominent place in organic chemistry textbooks of the future.

Source: Chemistry in Britain

Acknowledgements

Jeremy Harvey