Pericyclic Reactions

FIELDS OF STUDY: Organic Chemistry; Physical Chemistry

ABSTRACT

The processes of pericyclic reactions are described, and their importance in chemical synthesis is explained. Pericyclic reactions represent a simple means of producing six-membered rings in molecular structures that are not easily produced by other means.

Understanding Pericyclic Reactions

In pericyclic reactions, the reacting compounds reorganize the electrons in the bonds between their atoms to form a new ring structure in the product of the reaction. Such reactions are unusual in that they involve neither any ionic or free radical mechanism nor any nucleophiles (electron donors) or electrophiles (electron acceptors) as reagents, and they are generally not affected by catalysts or different solvents. Perhaps the most startling fact about pericyclic reactions is that they break and make multiple bonds at once in what is termed a "concerted mechanism." Pericyclic reactions are not triggered by another reagent in the reaction mixture; instead, they are frequently triggered by light (in photolysis) or heat (in thermolysis).

Concerted Reactions

Pericyclic reactions are equilibrium reactions in accordance with their nature as concerted reactions. In a concerted reaction, everything can be thought of as happening at once. For example, a compound containing a conjugated diene system based on 1,3-butadiene (C=C−C=C) can undergo electrocyclic ring closure. (A conjugated diene is a diene that has alternating double and single bonds and a p orbital on three or more successive carbon atoms, which allows their electrons to move freely through them.) In that process, electrons in the molecular orbitals shift all at once to produce a cyclobutene structure by forming a new bond between the two carbon atoms at the ends of the system, changing the C=C−C=C bond sequence to a C−C=C−C bond sequence. These changes take place all at the same time rather than in a step-by-step manner. This corresponding simultaneous change is typical of all pericyclic reactions.

A conjugated diene system is not an absolute requirement for a concerted pericyclic reaction to occur, although the vast majority of pericyclic reactions involve such a system. What is required is that the nonbonding p orbitals of the reacting components be in the correct positions so that electrons can shift through them effectively unhindered to form new bonds. Because pericyclic reactions are equilibrium reactions, the reverse must also be true: that is, the electrons in bonds must be able to shift unhindered through molecular orbitals to regenerate the nonbonding p orbitals and bonds of the original structures.

Types of Pericyclic Reactions

The best-known pericyclic reaction is the Diels-Alder reaction, named for its discoverers, German chemists Otto Diels (1876–1954) and Kurt Alder (1902–58), who reported it in the chemical literature in 1928. In a Diels-Alder reaction, a conjugated diene undergoes a concerted reaction with an activated alkene (unsaturated hydrocarbon with one or more C=C bonds) called a dienophile. The interaction forms two new bonds to connect the two carbon atoms of the dienophile to the two end carbons of the diene system. When this happens, the p orbitals of those four carbon atoms hybridize into the sp2 atomic orbitals to produce sp3 orbitals. At the same time, the electrons shift to form a pi (π) bond, or secondary covalent bond, with the two remaining p orbitals between the two interior carbon atoms of the diene system. In the end, where there was once a conjugated diene molecule and an alkene molecule, there is a single six-membered ring molecule with a C=C bond in its structure. The most basic example of the Diels-Alder reaction is the reaction between 1,3-butadiene and ethylene to form cyclohexene, with the C=C bond between the two carbon atoms that had been the second and third carbon atoms in the 1,3-butadiene molecule. A Diels-Alder reaction can take place within a single relatively large molecular structure in the same way that it would occur between two separate molecules. For this to occur, however, the bonds that would be taking part in the reaction must be able to assume the requisite spatial relationship.

Electrocyclic ring closure is another type of pericyclic reaction. In this type of reaction, the porbitals on the terminal carbon atoms of the butadiene structure behave in exactly the same way as in the Diels-Alder reaction: that is, they hybridize with the sp2 atomic orbitals to form sp3 orbitals that are part of a primary covalent, or sigma (σ), bond. In the electrocyclic reaction, the relative position of the two terminal carbon atoms determines whether a reaction takes place. Not surprisingly, electrocyclic ring closures can take place in more extensive conjugated systems as well. A compound in which three conjugated C=C bonds can assume the configuration of a six-membered ring can undergo electrocyclic ring closure. Electrons and orbitals shift to form a sigma bond between the two carbon atoms at either end of the conjugated triene system and a conjugated cyclohexadiene structure. In other molecules that are large enough, even three isolated C=C bonds that can assume the proper p orbital configuration can shift electrons and orbitals to form a six-membered ring. However, the more complex the molecular structure, the less likely it is that the appropriate configuration will be achieved.

Although pericyclic reactions do not function by an ionic mechanism, it is possible for certain ions to take part in electrocyclic reactions. The most common of these are termed "1,3-cycloadditions" and normally involve the transformation of a cyclopropyl ring structure and a carbocation in which the carbon atom carries the positive charge, called an "allyl cation." Ring strain in the cyclopropyl system imparts significant additional energy into the C−C bonds due to the difference in their actual bond angles and the ideal bond angles determined by the geometry of their atomic orbitals. There is thus a fairly strong incentive for the cyclopropyl ring to open up in an electrocyclic manner to form an allyl cation system (C=C−C⁺) when the structure of the molecule makes that possible.

Factors Affecting Pericyclic Reactions

Given that pericyclic reactions take place readily under the influence of either light or heat, it should not be surprising that compounds in which such reactions are possible easily become contaminated by the products of those reactions. Since all pericyclic reactions are equilibrium reactions, this sort of contamination is nearly impossible to avoid. In an equilibrium system, both the forward and the reverse reactions take place to attain a steady state in which constant quantities of both reactants and products are present. It is possible to prepare stable systems with the right components for a pericyclic reaction to occur, but the reaction is prevented from occurring by steric hindrance, the physical interference to the motion of atoms and other chemical components resulting from the physical size and restricted mobility of substituent groups, or side chains, within the molecular structure. The presence of relatively large substituent groups in the molecular structure can effectively prevent the orbitals in the conjugated system from attaining the proper trajectory for interaction to take place. The three orbitals about an sp2 hybridized carbon atom are arranged in a plane, with the p orbital perpendicular. For the two terminal p orbitals at the ends of the system to interact in an electrocyclic reaction, they must be able to rotate. Similarly, the p orbitals involved in a Diels-Alder reaction must be able to overlap. In both cases, the order of substituents about the two carbon atoms becomes rigidly fixed by the ring structure. Any substituent group that either physically gets in the way of orbital alignment or acts to stabilize the p orbitals can effectively prevent a pericyclic reaction from taking place.

Pericyclic Reactions in Synthesis

The use of pericyclic reactions in the synthesis of specific compounds demands that close attention be paid to the manner in which orbitals must be able to shift in order to come into the proper configuration for bond formation. This will determine the stereochemical (spatial) arrangement of substituents about the carbon atoms involved in the new bonds. The compound cantharidin is a naturally occurring compound produced as a defensive material by certain beetles. The three-dimensional structure of cantharidin immediately suggests that a simple Diels-Alder reaction between the compounds furan and 2,3-dimethylmaleic anhydride should yield the cantharidin structure directly. However, when researchers attempted to carry out this synthesis, the reaction failed, largely due to steric hindrance. Steric hindrance in the structure was sufficient to render the material unstable and drive the reverse reaction to re-form the starting materials. The actual synthesis of cantharidin, first successfully carried out by chemist Gilbert Stork in 1951, thus requires a prolonged series of transformations in order to produce a compound stereochemically identical to natural cantharidin.

As is often the case, equilibrium reactions are useful in synthesis but require some special considerations in order to obtain the best yields of their desired products. This is best achieved when the desired product can isolated in some way be from the reaction mixture as it is formed. In some cases, it is possible to carry out a reaction using a solvent in which the desired product is insoluble and so can be filtered out. In other cases, the product may be sufficiently volatile that it can be isolated by distillation as the reaction proceeds. However, in many cases, the chemist has no choice but to identify the stage in the reaction when the desired product is at its highest concentration, quench the reaction mixture to stop the reaction, and then separate and identify the various components in order to isolate the desired product of the reaction.

PRINCIPAL TERMS

• concerted reaction: a reaction that proceeds from starting materials to end products in a single molecular process rather than via a stepwise mechanism
• Diels-Alder reaction: a reaction in which an activated conjugated diene compound reacts with a suitable dienophile to form a six-membered ring structure; named for Otto Diels and Kurt Alder.
• diene: an organic compound that contains two carbon-carbon double bonds (C=C) in its molecular structure.
• dienophile: an organic compound containing a carbon-carbon double bond (C=C) that reacts preferentially with a suitable diene in a Diels-Alder reaction.

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