In chemistry, a reaction intermediate, or intermediate, is a molecular entity arising within the sequence of a stepwise chemical reaction. It is formed as the reaction product of an elementary step, from the reactants and/or preceding intermediates, but is consumed in a later step. It does not appear in the chemical equation for the overall reaction.^[1]

For example, consider this hypothetical reaction:

${\displaystyle {\ce {A + B -> C + D))}$

If this overall reaction comprises two elementary steps thus:

${\displaystyle {\ce {A + B -> X))}$

${\displaystyle {\ce {X -> C + D))}$

then X is a reaction intermediate.

The phrase itself, reaction intermediate, is very often abbreviated to the single word intermediate, and this is IUPAC's preferred form of the term.^[2] But this shorter form has other uses. It often refers to reactive intermediates. It is also used more widely for chemicals such as cumene which are traded within the chemical industry but are not generally of value outside it.

IUPAC definition

The IUPAC Gold Book defines^[3] an intermediate as a compound that has a lifetime greater than a molecular vibration, is formed (directly or indirectly) from the reactants, and reacts further to give (either directly or indirectly) the products of a chemical reaction. The lifetime condition distinguishes true, chemically distinct intermediates, both from vibrational states and from transition states (which, by definition, have lifetimes close to that of molecular vibration).

The different steps of a multi-step reaction often differ widely in their reaction rates. Where the difference is significant, an intermediate consumed more quickly than another may be described as a relative intermediate. A reactive intermediate is one which due to its short lifetime does not remain in the product mixture. Reactive intermediates are usually high-energy, are unstable and are seldom isolated.

Common reaction intermediates

Carbocations

Cations, often carbocations, serve as intermediates in various types of reactions to synthesize new compounds.

Carbocation intermediates in alkene addition

Carbocations are formed in two major alkene addition reactions. In an HX addition reaction, the pi bond of an alkene acts as a nucleophile and bonds with the proton of an HX molecule, where the X is a halogen atom. This forms a carbocation intermediate, and the X then bonds to the positive carbon that is available, as in the following two-step reaction.^[4]

CH₂CH₂ + HX → CH₂CH₃⁺ + X^-

CH₂CH₃⁺ + X^- → CH₂XCH₃

Similarly, in an H₂O addition reaction, the pi bond of an alkene acts as a nucleophile and bonds with the proton of an H₃O⁺ molecule. This forms a carbocation intermediate (and an H₂O atom); the oxygen atom of H₂O then bonds with the positive carbon of the intermediate. The oxygen finally deprotonates to form a final alcohol product, as follows.^[4]

CH₂CH₂ + H₃O⁺ → CH₂CH₃⁺ + H₂O

CH₂CH₃⁺ + H₂O → CH₂OH₂CH₃⁺

CH₂OH₂CH₃⁺ + H₂O → CH₂OHCH₃ +H₃O⁺

Carbocation intermediates in nucleophilic substitution

Nucleophilic substitution reactions occur when a nucleophilic molecule attacks a positive or partially positive electrophilic center by breaking and creating a new bond. S_N1 and S_N2 are two different mechanisms for nucleophilic substitution, and S_N1 involves a carbocation intermediate. In S_N1, a leaving group is broken off to create a carbocation reaction intermediate. Then, a nucleophile attacks and forms a new bond with the carbocation intermediate to form the final, substituted product, as shown in the reaction of 2-bromo-2-methylpropane to form 2-methyl-2-propanol.^[4]

(CH₃)₃CBr → (CH₃)₃C⁺

(CH₃)₃C⁺ + H₂O → (CH₃)₃OH₂⁺

(CH₃)₃OH₂⁺ → (CH₃)₃OH + H⁺

In this reaction, (CH₃)₃C⁺ is the formed carbocation intermediate to form the alcohol product.

Carbocation intermediates in elimination reactions

β-elimination or elimination reactions occur through the loss of a substituent leaving group and loss of a proton to form a pi bond. E1 and E2 are two different mechanisms for elimination reactions, and E1 involves a carbocation intermediate. In E1, a leaving group detaches from a carbon to form a carbocation reaction intermediate. Then, a solvent removes a proton, but the electrons used to form the proton bond form a pi bond, as shown in the pictured reaction on the right.^[4]

Carbanions

A carbanion is a organic molecule where a carbon atom is not electron deficient but contain an overall negative charge. Carbanions are strong nucleophiles, which can be used to extend an alkene's carbon backbone in the synthesis reaction shown below.^[5]

C₂H₂ with NaNH₂ in NH₃ (l) → CHC^-

CHC^- + BrCH₂CH₃ → CHCCH₂CH₃

The alkyne carbanion, CHC^-, is a reaction intermediate in this reaction.^[4]

Radicals

Radicals are highly reactive and short-lived, as they have an unpaired electron which makes it extremely unstable. Radicals often react with hydrogens attached carbon molecules, effectively making the carbon a radical while stabilizing the former radical in a process called propagation. The formed product, a carbon radical, can react with non-radical molecule to continue propagation or react with another radical to form a new stable molecule such as a longer carbon chain or an alkyl halide.^[4]

The example below of methane chlorination shows a multi-step reaction involving radicals.

Methane chlorination

Methane chlorination is a chain reaction. If only the products and reactants are analyzed, the result is:

${\displaystyle {\ce {CH4 + 4Cl2->CCl4 +4HCl))}$

However, this reaction has 3 intermediate reactants which are formed during a sequence of 4 irreversible second order reactions until we arrive at the final product. This is why it's called a chain reaction. Following only the carbon containing species in series:

${\displaystyle {\ce {CH4 -> CH3Cl -> CH2Cl2 -> CHCl3 -> CCl4))}$

Reactants: ${\displaystyle {\ce {CH4 + 4Cl2))}$

Products: ${\displaystyle {\ce {CCl4 + 4HCl))}$

The other species are reaction intermediates: ${\displaystyle {\ce {CH3Cl, CH2Cl2, CHCl3))}$

These are the set of irreversible second-order reactions:

${\displaystyle {\ce {CH4 + Cl2->CH3Cl + HCl))}$

${\displaystyle {\ce {CH3Cl + Cl2->CH2Cl2 + HCl))}$

${\displaystyle {\ce {CH2Cl2 + Cl2->CHCl3 + HCl))}$

${\displaystyle {\ce {CHCl3 + Cl2->CCl4 + HCl))}$

These intermediate species’ concentrations can be calculated by integrating the system of kinetic equations. The full reaction is a free radical propagation reaction which is filled out in detail below.

Initiation: This reaction can occur by thermolysis (heating) or photolysis (absorption of light) leading to the breakage of a molecular chlorine bond.

${\displaystyle {\ce {Cl-Cl ->[h \nu] Cl. + Cl.))}$

When the bond is broken it produces two highly reactive chlorine atoms.

Propagation: This stage has two distinct reaction classes. The first is the stripping of a hydrogen from the carbon species by the chlorine radicals. This occurs because chlorine atoms alone are unstable, and these chlorine atoms react with one the carbon species' hydrogens. The result is the formation of hydrochloric acid and a new radical methyl group.

${\displaystyle {\ce {CH3-H + Cl. -> CH3. + H-Cl))}$

${\displaystyle {\ce {CH2Cl-H + Cl. -> CH2Cl. + H-Cl))}$

${\displaystyle {\ce {CHCl2-H + Cl. -> CHCl2. + H-Cl))}$

${\displaystyle {\ce {CCl3-H + Cl. -> CCl3. + H-Cl))}$

These new radical carbon containing species now react with a second Cl₂ molecule. This regenerates the chlorine radical and the cycle continues. This reaction occurs because while the radical methyl species are more stable than the radical chlorines, the overall stability of the newly formed chloromethane species more than makes up the energy difference.

${\displaystyle {\ce {CH3. + Cl-Cl -> CH3Cl + Cl.))}$

${\displaystyle {\ce {CH2Cl. + Cl-Cl -> CH2Cl2 + Cl.))}$

${\displaystyle {\ce {CHCl2. + Cl-Cl -> CHCl3 + Cl.))}$

${\displaystyle {\ce {CCl3. + Cl-Cl -> CCl4 + Cl.))}$

During the propagation of the reaction, there are several highly reactive species that will be removed and stabilized at the termination step.

Termination: This kind of reaction takes place when the radical species interact directly. The products of the termination reactions are typically very low yield in comparison to the main products or intermediates as the highly reactive radical species are in relatively low concentration in relation to the rest of the mixture. This kind of reaction produces stable side products, reactants, or intermediates and slows the propagation reaction by lowering the number of radicals available to propagate the chain reaction.

There are many different termination combinations, some examples are:

Union of methyl radicals from a C-C bond leading to ethane (a side product).

${\displaystyle {\ce {CH3. + CH3. -> CH3-CH3))}$

Union of one methyl radical to a Cl radical forming chloromethane (another reaction forming an intermediate).

${\displaystyle {\ce {CH3. + Cl. -> CH3Cl))}$

Union of two Cl radicals to reform chlorine gas (a reaction reforming a reactant).

${\displaystyle {\ce {Cl. + Cl. -> Cl2))}$

Applications

Biological intermediates

Reaction intermediates serve purposes in a variety of biological settings. An example of this is demonstrated with the enzyme reaction intermediate of metallo-β-lactamase, which bacteria can use to acquire resistance to commonly used antibiotics such as penicillin. Metallo-β-lactamase can catalyze β-lactams, a family of common antibiotics. Spectroscopy techniques have found that the reaction intermediate of metallo-β-lactamase uses zinc in the resistance pathway.^[6]

Another example of the importance of reaction intermediates is seen with AAA-ATPase p97, a protein that used in a variety of cellular metabolic processes. p97 is also linked to degenerative disease and cancer. In a study looking at reaction intermediates of the AAA-ATPase p97 function found an important ADP.P_i nucleotide intermediate is important in the p97 molecular operation.^[7]

An additional example of biologically relevant reaction intermediates can be found with the RCL enzymes, which catalyzes glycosidic bonds. When studied using methanolysis, it was found that the reaction required the formation of a reaction intermediate.^[8]

Chemical processing industry

In the chemical industry, the term intermediate may also refer to the (stable) product of a reaction that is itself valuable only as a precursor chemical for other industries. A common example is cumene which is made from benzene and propylene and used to make acetone and phenol in the cumene process. The cumene itself is of relatively little value in and of itself, and is typically only bought and sold by chemical companies.^[9]