Conformation searching

• Conformers are isomers which have the same connectivity, but differ in bond rotation positions.  This includes ring flipping
• You may be trying to model the most stable conformer, or you may wish to model several of the more stable, which you presume are in equilibrium with each other
• Generally, your knowledge as a chemist will allow you to hypothesize roughly the structures of the conformer(s) you are seeking
• Start by putting together your rough model as close to your hypothesized structure as you have patience for, using the facilities for bond rotation provided in the modelling package you are using.  If you start geometry optimisation from close to your hypothesized structure, this improves the chance that it will converge to that conformer rather than a different one.
• You may find that however close your starting point is, the minimisation routine always goes somewhere else.  In that case, for the modelling method you are using, and the minimisation software you are using, your hypothesis was wrong.  If there is an energy minimum at that geometry, it is too shallow to be found.
• A much more important problem is that, after all this, there are one or more important conformers which you have not thought of, and which the minimisation routine has not found by accident
• You must make a sensible search for other conformers, otherwise you have not modelled the system
• The more elaborate modelling programs can do this automatically:  one popular method is the Monte Carlo method, as follows
• The program starts from an already found conformer
• Random changes are made to bond rotations
• Geometry is optimised, starting from each such new point
• A list is kept of found conformers
• When each conformer has been found at least twice, the program stops
• Even with a powerful computer and a fast method, this can take hours or days for a large molecule
• If you do not have a program to do it for you, you should attempt a manual conformer search:  you need to consider
• bond rotation
• ring flipping (which involves several bond rotations at the same time)
• inversion at atoms with lone pairs, usually N, P, S
• Make a list of what you plan to do, before you start, to make sure you cover all the combinations, however unreasonable they may seem to you.  Tick off and annotate the list as you proceed.

Bond rotation

• You do not need to rotate methyl groups, because all rotamers they can minimise to are the same
• You do need to rotate:
• any unsymmetrically substituted C, e.g. CH₂Me
• all OH groups (there could be H bonding in some positions, as well as preferred p bonding orientations for any OR group)
• all amine groups
• If you have two independent phenyl groups in a molecule, they often prefer to have their planes perpendicular to each other if possible
• Amide NRR' groups are usually planar, with a delocalised lone pair.  If R is not equal to R', try turning the group through 180 degrees

Ring flipping

• You have to break the ring, rotate some bonds to different rotamers, then join it up again
• You need only consider rotamers for which some further, different rotation will allow the ring to be rejoined
• Go round the ring systematically

Inversion

• Unless there are big groups on N, inversion tends to be fast on the NMR timescale.  However, you still need to find out whether the two invertomers have similar enough energies for both to be important models
• If the N is nearly flat, the minimisation routine may always jump through to the more stable invertomer, so you may not be able to find out about both
• Three coordinate P or S invert much more slowly, and both invertomers may be isolatable on the laboratory timescale.  You need to model both.