Question

The amino acid methionine is formed by a methylation reaction of homocysteine with N-methyltetrahydrofolate. The stereochemistry of the reaction has been probed by carrying out the transformation using a donor with a “chiral methyl group” that contains protium (H), deuterium (D), and tritium (T) isotopes of hydrogen. Does the methylation reaction occur with inversion or retention of configuration?

Short answer

Retention

Step-by-step solution

R and S- configuration

For determining R and S configuration, the direction of the top 3 priorities is seen from highest to lowest priority.

A counterclockwise direction means S configuration, and a clockwise direction means R configuration.

Sequence Rules for Specifying Configuration

• Rule 1

The priority in numbering is given to the directly attached atom having the highest atomic number. The highest ranking(first)is given to the atom with the highest atomic number, and the lowest ranking (fourth) is given to the atom with the lowest atomic number.

• Rule 2

If the first directly attached atoms have the same atomic number in substituent and a decision cannot be made, then look for the difference at the second, third, or fourth directly attached atoms at chiral carbon until you find a difference.

• Rule 3

If two atoms are multiple-bonded, it is counted as equivalent to the same number of single-bonded atoms.

• After the ranking of the four groups at a chiral center is completed, the next step is to orient the lowest priority group on the rear side and then check the priority order of the remaining three groups from 1 to 3 priority numbering by drawing a curved arrow.

• Suppose a curved arrow is drawn from the highest to second-highest to third-highest ranked substituent and is clockwise. In that case, the chirality center has the Rconfiguration, and if the arrow is counterclockwise, then the Sconfiguration.

• In case when lowest priority group is not on the rear side, then a double interchange is done: one between the rear group and the lowest priority group and one between the other two groups to know their configuration

Isotope and reaction type

Here three isotopes of hydrogen are used in which protium (H) has the least atomic number, then deuterium (D) and then tritium (T), which has the highest atomic number. The reaction occurring here is a ${\mathrm{SN}}_2$ reaction which causes inversion.

Methionine

The methionine structure shown in the figure has four groups attached H, D, T and S. S has the highest atomic number, then T after it D and at last H. Here, the lowest priority group is not on the rear side, so that the double inter-conversion will occur. Methionine here has an R configuration as clockwise ranking is present.

N-Methyltetrahydrofolate

N-Methyltetrahydrofolate structure in the figure has four groups attached H, D, T and N. N has the highest atomic number than T, D, and at last, H. Here, the lowest priority group is in the plane, not on the rear side, so double inter-conversion will occur.

N-Methyltetrahydrofolate has an R configuration as a clockwise ranking is present.

Conclusion

As in both N-Methyltetrahydrofolate and Methionine, R-configuration is present, so two inversions occur. Hence net retention of configuration is seen. This retention in configuration is because two inversions give retention configuration.