Substitution Reaction
A substitution reaction is a fundamental type of chemical process where one atom or functional group in a molecule is replaced by another. This reaction is characterized by the adherence to specific stereochemical rules, allowing for precise control over the resulting molecular structure. There are two primary types of substitution reactions: nucleophilic and electrophilic.
In nucleophilic substitution, a nucleophile displaces a leaving group from a substrate molecule. This can happen in two main ways: the S N 2 mechanism involves a simultaneous bond formation and breaking, resulting in an inversion of configuration, while the S N 1 mechanism features a two-step process wherein a carbocation intermediate forms before the nucleophile attaches, often resulting in a mixture of products.
Electrophilic substitution, on the other hand, typically involves electron-rich compounds, particularly those with aromatic structures. In this case, an electrophile interacts with the molecule, leading to the substitution of hydrogen atoms with other groups. Substitution reactions also play crucial roles in biological systems, where enzymes facilitate modifications to enhance the solubility and transport of various compounds. Understanding these reactions is essential in both synthetic chemistry and pharmacology.
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Substitution Reaction
FIELDS OF STUDY: Biochemistry; Genetics; Molecular Biology
ABSTRACT
The processes of substitution reactions are described, and their value in synthesis is elaborated. Substitution reactions strictly adhere to stereochemical rules, permitting precise control of the molecular structure of the product.
The Basics of Substitution Reactions
Substitution reactions are easily recognized by the replacement of one substituent—an atom or functional group—in a reactant compound with a different group at the same position in the molecular structure. Substitution always replaces one component of a molecule with a different component not initially part of the molecule. The process must take place according to the same rules of chemical behavior that control the formation of a compound. When a compound undergoes a substitution reaction, the affected portion of the compound reacts in specific ways determined by the basic rules of chemical behavior. Two modes of substitution reactions are known: nucleophilic and electrophilic.
Nucleophilic Substitution
In nucleophilic substitution reactions, a nucleophile reacts with a substrate molecule (the molecule being acted upon) and replaces one of its existing substituents. The replaced substituent is known as the leaving group because it leaves the molecular structure when the substitution occurs. Substitution reactions require a substrate molecule with a suitable functional group, typically one that can become the leaving group.
A nucleophile is a chemical species that is attracted to, or reacts preferentially at, a species with a strong positive charge or a location with enhanced positive-charge character. A chemical bond between a carbon atom (C) and an iodine atom (I), for example, is polarized by the higher electronegativity (tendency to attract electrons) of the iodine atom. As a result, the carbon atom has a lower electron density and therefore more positive charge. In basic conditions, a hydroxide ion (OH−), which has a high electron density and thus a negative charge, is able to associate with the carbon atom, as the opposite charges attract. The electron density of the hydroxide ion is greater than that of the iodine atom, which is sufficient to force the electrons in the C−I bond to shift toward the oxygen atom of the hydroxide ion and form a C−O bond. The reactants pass through a transition state as the bond to the oxygen atom strengthens and the bond to the iodine atom weakens. Since the four substituents bonded to a carbon atom in an organic molecule are arranged tetrahedrally about the carbon atom, the arrangement of the substituents is unique. Substitution reactions that occur in this manner are called SN2 reactions (for "substitution nucleophilic bimolecular") and always conclude with an inversion of the original substituent arrangement about the carbon atom. This inversion is analogous to an umbrella being blown inside out by a strong wind. In a synthesis process, the inversion requirement is used to determine the stereochemistry of the product. The term "bimolecular" refers to the dependency of the rate of the reaction on the concentrations of both the nucleophile and the substrate.
A second mode of nucleophilic substitution occurs under acidic conditions. An organic alcohol (R−OH), for example, can be converted to an alkyl chloride by strong hydrochloric acid (HCl). Under the conditions of the reaction, the oxygen atom of the hydroxyl (−OH) group in the alcohol molecule acquires an additional proton in the form of a hydrogen cation (H+), forming the intermediate structure R−OH2+. This species can release either the H+, thus re-forming the original alcohol, or a neutral water molecule (H2O), thus forming the corresponding carbonium ion R+. A carbonium ion can do three things: rearrange its bonds and overall structure to form a more stable carbonium ion before reacting further, eject another H+ to form a double bond (which would result in an elimination reaction), or gain a nucleophile. In this example, the chloride (Cl−) ion of the hydrochloric acid acts as a nucleophile and forms a bond to the carbon atom of the carbonium ion to yield the alkyl chloride R−Cl. This type of substitution is termed SN1, for "substitution nucleophilic unimolecular," meaning that the reaction rate depends only on the concentration of the substrate compound. The product of an SN1 reaction is typically an equal mixture of molecules in which the substituents are inverted and molecules that retain their original arrangement , which reduces the efficiency of the substitution reaction by 50 percent, unless the orientation of the product molecules is not important.
Electrophilic Substitution Reactions
In electrophilic substitution reactions, the electrophile typically has a high degree of Lewis acidity, meaning that it has an affinity for negative charge and reacts readily with electron-rich chemical species. Electrophilic substitution reactions typically involve compounds with conjugated double-bond systems, especially the aromatic six-membered ring structure of the benzene molecule. Such compounds are notable for being otherwise unreactive. For example, in an electrophilic substitution reaction involving an aromatic compound such as toluene, which is a benzene molecule in which one of the hydrogen atoms has been replaced by a methyl group substituent (−CH3), the electrophile coordinates to one of the pi bonds of the six-membered ring. Often a Lewis acid material, such as aluminum chloride (AlCl3) or iron(III) chloride (FeCl3), catalyzes such reactions, and the electrophilic species is added to one of the carbon atoms of the ringto form a charge-separated intermediate compound. Loss of the hydrogen atom or its relocation within the molecule affects the substitution reaction. When toluene reacts with "fuming sulfuric acid," a solution of sulfur trioxide (SO3) in concentrated sulfuric acid (H2SO4), a molecule of sulfur trioxide is added to the toluene ring in such a way that one of its pi bonds gives up an electron, giving the toluene a positive charge, and the sulfur trioxide group acquires a negative charge by accepting the electron. Therefore, the carbon atom is bonded to both a hydrogen atom and the sulfur trioxide group. The hydrogen atom subsequently shifts, bonding to an oxygen atom of the sulfur trioxide group. The result is the formation of toluene sulfonic acid, in which a hydrogen atom has been substituted by the −SO3H group.
Substitution Reactions in Biological Systems
In both chemistry laboratories and chemical engineering applications, substitution reactions typically take place between the chemical compounds themselves. In biological systems, however, substitution reactions are moderated by enzymes that carry out specific modifications. The modification of various compounds through metabolism functions primarily to enhance the solubility of the compounds in the aqueous medium of body fluids and to improve their ability to pass through cell membranes. Bile acids are added to various compounds to facilitate their removal from the body by the kidneys. Enzyme actions bring about the substitution of the bile acid for some substituent on a metabolite compound. Pharmacologists work to understand this process and how it affects the activity and effectiveness of different drugs considered for use as medicines.
PRINCIPAL TERMS
- electrophilic: describes a chemical species that tends to react with negatively charged or electron-rich species.
- functional group: a specific group of atoms with a characteristic structure and corresponding chemical behavior within a molecule.
- intermediate: a relatively stable but reactive chemical species that is formed during a chemical reaction and either reverts to the original reactants or continues in the reaction mechanism to form products.
- leaving group: an atom or group of atoms that is removed from a molecule during a chemical reaction, along with the electron pair that previously bonded it to the molecule.
- nucleophilic: describes a chemical species that tends to react with positively charged or electron-poor species.
Bibliography
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