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. 2024 Sep 20;89(18):13485-13490.
doi: 10.1021/acs.joc.4c01673. Epub 2024 Sep 6.

Relative Rates of Transesterification vis-à-vis Newman's Rule of Six

Arianna M H Wheeler  1 , Sei-Chang Ahn  1 , Niklas Kraemer  1 , Thomas R Hoye  1
Affiliations

Relative Rates of Transesterification vis-à-vis Newman's Rule of Six

Arianna M H Wheeler et al. J Org Chem. .

Abstract

The relative reactivity of a systematic series of simple aliphatic acetate esters has been measured. Exposure of pairs of esters of increasing remote steric hindrance (by altering the degree of branching of the ester alkyl group) to a methanolic solution of Cs2CO3 proved to be a reliable (and general) method for quantitating the rate differences in these base-catalyzed transesterification reactions. The trends in relative rates are in accordance with the qualitative "Rule of Six" put forward by Melvin S. Newman in 1950, as deduced then from interpretation of earlier reports of ease of Fischer esterification reactions.

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Conflict of interest statement

None of the authors have a competing financial interest in this work.

Figures

Figure 1.
Figure 1.
(a) A generic structure in which the rule of six can be considered for the reactivity of addition reactions to the C=X moiety. (b) Three (of the dozens) of Fischer esterification reactions that Newman drew upon in developing his empirical rule of six. (c) An example showing the benefit of understanding the role of remote steric hindrance.
Figure 2.
Figure 2.
Ten model acetates ranging from zero [6H/0C] to six [0H/6C] carbons in the six-position were studied.
Figure 3.
Figure 3.
An example of the data collection for one trial (a) of 6 vs. 7b. (b) Time zero spectrum from which the initial ratios of each acetate vs. the mesitylene standard were measured. (c) Spectra of aliquots taken over time. (d) Plot of the consumption of each of acetates 6 and 7b over time.
Figure 4.
Figure 4.
Conformational analysis of the lowest energy conformers of 9a (2,2-dimethyl-3-pentyl acetate) and 9b (2,4-dimethyl-3-pentyl acetate).
Figure 5.
Figure 5.
Relative rates of Brønsted acid-catalyzed methanolysis for the acetates 6, 7b, and 8b.
See this image and copyright information in PMC

References

    1. Newman MS Some observations concerning steric factors. J. Am. Chem. Soc 1950, 72, 4783–4786.
    1. Bhide BV; Sudborough JJ Studies in transesterification. J. Ind. Inst. Sci 1925, 8, 89–128.
    2. von Braun J; Fischer F Beiträge zur Kenntnis der sterischen Hinderung, VII. Mitteil.: Veresterung und Verseifung vom Standpunkt der elektronischen Theorie der Bindung. Chem. Ber 1933, 66, 101–104.
    3. Smith HA; Burn J Kinetics of the acid-catalyzed esterification of phenyl- and cyclohexyl-substituted aliphatic acids in methanol. J. Am. Chem. Soc 1944, 66, 1494–1497.
    1. Newman MS Additions to unsaturated functions. In Steric Effects in Organic Chemistry; John Wiley & Sons, 1956; pp 201–248.
    1. This type of longer-range steric effect (or wrap-around effect) is similar to what is learned from the A-values in the monoalkylcyclohexanes (i.e., 1.7 Me to 1.8 Et to 2.2 iPr to ~5 tBu kcal mol−1); Anslyn EV; Dougherty DA Strain and stability. In Modern Physical Organic Chemistry; University Science, 2005; pp 65–143.

    2. (b) The change of iPr to tBu introduces, perforce, a methyl carbon in place of a hydrogen that is six atoms removed from the axial hydrogen atoms at C3 and C5 of the cyclohexane ring.

    1. A Google Scholar search (6–27-24) for “rule of six” within the 196 articles that cite reference #1 resulted in 61 hits, of which approximately half are in the context of polymer chemistry.

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