4.10: Reactions with cyclic transition state

Learning Objectives

• Learn examples of reactions that involve five- or six-member transition state, including cyclonic hemiacetal formation of monosaccharides, Diels-Alter reactions producing six-membered cyclic products, and decarboxylation of \(\beta\)-keto acids.

Intramolecular reactions happen if the two reacting groups are on the same molecule and can come to a bonding distance through a five- or six-member cyclic transition state. Some examples of it are described in the next sections.

Cyclic hemiacetal formation of monosaccharides

Monosaccharides, like glucose, fructose, galactose, etc., have a \(\ce{C=O}\)-group on one \(\ce{C}\) and \(\ce{-OH}\)-group on every other \(\ce{C}\). \(\ce{-OH}\)-group can add to \(\ce{C=O}\)-group forming a hemiacetal. Monosaccharides exist primarily in a five- or six-membered hemiacetal form because one of their \(\ce{-OH}\)-group can form a five- or six-membered transition state for the reaction, as shown in Figure \(\PageIndex{1}\) for the case of D-glucose and D-fructose.

Figure \(\PageIndex{1}\): Illustration of five- or six-member cyclic hemiacetal formation of D-glucose and D-fructose through a cyclic transition state. (Copyright; Glucose: Calvero (talk · contribs), Public domain, via Wikimedia Commons, and Fructose: Vaccinationist, Public domain, via Wikimedia Commons)

Diels–Alder reaction

A conjugated diene, e.g., butadiene, and an alkene, e.g., ethene, make a cyclic six-member transition state. They react by the Diels-Alder reaction mechanism and produce a six-member cyclic product. This reaction can be intermolecular, e.g., between butadiene and then, or intramolecular, e.g., in the biosynthesis of antibiotic lovastatin, illustrated in Figure \(\PageIndex{2}\).

Figure \(\PageIndex{2}\): Mechanism of Diels-Alter reaction illustrated with the example of reaction between butadiene and ethene (left) and biosynthesis of lovastatin (right). Three \(\pi\)-bonds break, and two \(\sigma\)-bonds and one \(\pi\)-bond form, shown in blue. (Copyright: Public domain)

Decarboxylation

Decarboxylation is the removal of carbon dioxide (\(\ce{CO2}\)) from a carboxylic acid (\(\ce{R-COOH}\)), as in this example: \(\ce{R-COOH ->[\Delta] R-H + CO2}\).

This reaction requires high temperatures, such as in the thermal decomposition process. However, if there is a second carbonyl (\(\ce{C=O}\))) group \(\beta\}\) to the \(\ce{-COOH}\) group, it can easily acquire a six-member transition state and decarboxylate at moderate temperatures, as illustrated in Figure \(\PageIndex{3}\).

Figure \(\PageIndex{3}\): Decarboxylation mechanism of \(\beta\)-keto carboxylic acids illustrated with the example decarboxylation of acetoacetic acid. (Copyright: Public domain).

Ketone bodies and diabetes mellitus

Acetoacetic acid and its reduced product \(\beta\)-hydroxybutyric acid, shown below, are produced in the liver as a result of the metabolism of fatty acids and some amino acids.

Acetoacetic acid and \(\beta\)-hydroxybutyric acid are called ketone bodies. Their concentration in the blood of healthy persons is about 0.01 mmol/L but in persons suffering from starvation or diabetes mellitus may be up to 500 times higher.

Carboxylic acids exist as carboxylate anions under physiological conditions. Decarboxylation of the \(\beta\)-keto carboxylates happens spontaneously under physiological conditions. For example, acetoacetate decarboxylates and produces carbon dioxide and acetone, as illustrated in Figure \(\PageIndex{4}\).

Figure \(\PageIndex{4}\): Illustration of decarboxylation mechanism with the example of acetoacetate converting into carbon dioxide and acetone. (Copyright; Public domain)

Carbon dioxide leaves under moderate conditions in this case because the anion left behind is in resonance with the \(\beta\)-\(\ce{C=O}\) group. The body does not metabolize acetone but exhales through the lungs. Acetone is responsible for its characteristic sweet smell in the breath of people with swear diabetes.