Mechanism of three-membered lactone hydrolysis in base

Chemistry Asked on January 4, 2022

I was reading up on the participation of neighboring functional groups and in the reaction below, I was wondering why hydroxide attacks the C–O bond instead of the carbonyl group of the lactone. Lactones tend to be more electrophilic compared to acyclic esters, as the lone pairs on the ether oxygen are not positioned correctly to participate in conjugation, so I would expect hydroxide to attack the carbonyl. Does it have to do with the angle of attack, given the small ring?

According to Organic Chemistry: Second Edition,[1, pg 934](from which I assume that the question was taken):

Enantiomerically pure (R)-2-bromopropanoic acid reacts with concentrated sodium hydroxide to give (S)-lactic acid. The reaction goes with inversion and is a typical SN2 reaction—and a good one too, since the reaction centre is adjacent to a carbonyl group. If, on the other hand, the reaction is run using $$ce{Ag2O}$$ and a low concentration of sodium hydroxide, (R)-lactic acid is obtained — there is overall retention of stereochemistry.

Therefore this reaction that has been questioned takes place at a low concentration of $$ce{OH-}$$ in the presence of $$ce{Ag2O}$$.

How do we decide between competing mechanisms?

The next paragraph clearly outlines what we need to look for in order to proceed.

In the first, we have conditions suited to an SN2 reaction: a very good nucleophile ($$ce{OH-}$$) and a good leaving group ($$ce{Br-}$$). Improve the leaving group by adding $$ce{Ag+}$$ ($$ce{Ag+}$$ assists $$ce{Br-}$$'s departure much as $$ce{H+}$$ assists the departure of $$ce{OH-}$$ by allowing it to leave as $$ce{H2O}$$) and worsen the nucleophile ($$ce{H2O}$$ instead of $$ce{OH-}$$, of which there is now only a low concentration), and we have the sorts of conditions that would favour an SN1 reaction. The trouble is, without neighbouring group participation, the cation here would be rather unstable — right next to a carbonyl group. The carboxylate saves the day by participating in the departure of the $$ce{Br-}$$ and forming the lactone. The key thing to remember is that a reaction always goes by the mechanism with the fastest rate.

From what I have understood the question lies in the step after the lactone is formed. What reacts, $$ce{C-1}$$ or $$ce{C-2}$$? Let's assume that both are possible and proceed with the two possible cases.

Firstly, the $$ce{OH-}$$ attacks the carboxylic carbon($$ce{C-1}$$). We get the possible reaction mechanism to be:

In the second case, let's assume that $$ce{OH-}$$ attacks $$ce{C-2}$$. The possible reaction mechanism would be:

So, now we are faced with the choice of which reaction could take place, attack on $$ce{C-1}$$ or attack on $$ce{C-2}$$.

From the second quotation, we can say that if we are able to decide which is faster, that would be the reaction that takes place and so we reach our next question.

Which reaction is faster?

In pathway 1, we are talking about the base hydrolysis of esters. However, esters are not very reactive and the concentration of base in this case is low as well.

In pathway 2, we are talking about an SN2 reaction taking place on the $$ce{C-2}$$ carbon which removes the ring strain that is seen in the lactone. Therefore, this would be faster than base hydrolysis that takes place at $$ce{C-1}$$

Another way of checking the speed of the reaction would be to use the principle of least motion, (as pointed out by Yusuf Hassan).

According to Advances in Physical Organic Chemistry, the principle of least motion is defined as:

The principle of least motion, states that those elementary reactions will be favored that involve the least change in atomic position and electronic configuration.

Using this, we can compare the relative rates of the two reactions.

During the base hydrolysis of esters, the hybridisation of the $$ce{C-1}$$ carbon changes from $$mathrm{sp^2}$$ to $$ce{sp^3}$$. This leads to a big change in the atomic arrangements since you go from a trigonal planar configuration to a tetrahedral arrangement.

In case of the SN2 reaction on the $$ce{C-2}$$ carbon, the configuration as a whole doesn't change. It remains $$mathrm{sp^3}$$ throughout the reaction, so there is less rearrangement taking place.

This implies that according to the principle of least motion, the SN2 reaction is favoured over the the basic hydrolysis of the lactone formed via the anchimeric effect.

Hence, we can say that the reaction that would take place would be the attack on $$ce{C-2}$$ and not the basic hydrolysis of the lactone.

Reference:

1. Organic Chemistry: Second Edition; Jonathan Clayden, Nick Greeves, Stuart Warren, 2014; ISBN 978-0198728719

Answered by Safdar Faisal on January 4, 2022

Related Questions

Acidic strength of organic acids. Substituted PhCOOH acids

1  Asked on December 19, 2020 by strawberry-sunshine

Help in understanding first law of thermodynamics?

0  Asked on December 17, 2020 by robert-patrick

phase equilibrium diagram

0  Asked on December 15, 2020 by user102151

Lewis structure of dinitrogen trioxide

2  Asked on December 10, 2020 by rasputin

When converting between a hydrated electrolyte amount in mass and in milliequivalents (meq), why are the water molecules taken into account?

1  Asked on December 8, 2020 by don_s

Extrapolating from a calorimetry lab to find a new delta T with different volumes and grams of substance

1  Asked on December 7, 2020 by catdog

Kinetics question regarding Rate Law

1  Asked on December 5, 2020 by tony-stark

Clar’s rule of polycyclic aromatic hydrocarbons

0  Asked on December 4, 2020 by mohamed

Adsorption of Cu2+ using banana peels for pH 2,2.5,3,3.5,4

0  Asked on December 4, 2020 by brien-lim

Unusual hydrolysis of methyl 2,4,6‐trimethylbenzoate

1  Asked on December 2, 2020 by harry-scamander

Identity a metal based on its properties

2  Asked on November 18, 2020 by abc

Bond Lengths: Equatorial vs Axial in Trigonal Bipyramidal

1  Asked on October 31, 2020 by sourav-suman

Water purification procedure that does not involve a flocculant of any kind?

2  Asked on October 26, 2020 by vokby

How do I calculate the isoelectric point of amino acids, each of which has more than two values of pKa?

1  Asked on October 16, 2020 by andrew-wolf

What is reaction between isopropyl alcohol and acetone?

3  Asked on October 1, 2020 by khaliddhali

Why can’t the reaction of grignard reagent with carboxylic acid give a ketone?

2  Asked on September 24, 2020 by abhishek-mhatre

Wavelength of X-rays

2  Asked on September 22, 2020 by user2619

Hydrogen peroxide bleaches litmus

0  Asked on September 21, 2020 by psix

Tollen’s Test with Salicylaldehyde

1  Asked on August 9, 2020 by aurav-s-tomar

Microanalytical Chemistry: Protocols for preparing low-volume calibration standards

0  Asked on July 27, 2020 by m-farooq