What is an intermediate?

REACH categorizes an intermediate as “a substance created for and utilized during chemical processes, ultimately transforming into a different substance.” This definition implies that an intermediate is actively involved in a chemical reaction and does not remain in the final product. Consequently, exposure of humans and the environment to this substance is minimized, particularly when managed under strictly controlled conditions.

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Note: When a chemical process does not result in the creation of another substance but instead yields mixtures, articles, or achieves a specific function or property, the substances involved are not considered intermediates.

Within REACH parameters, three kinds of intermediates are identified:

• Non-Isolated Intermediate: “An intermediate that is not intentionally removed (except for sampling) from the setup in which the synthesis is occurring.”
• On-Site Isolated Intermediate: “An intermediate not fulfilling the criteria of a non-isolated intermediate, produced and used at the same location by one or more entities.”
• Transported Isolated Intermediate: “An intermediate that does not meet the criteria of a non-isolated intermediate and is transported between different sites.”

Understand why your substance supplier may ask you to sign a statement ensuring compliance with transported isolated intermediates under strictly controlled conditions.

Molecular entities formed as intermediate steps in complex chemical reactions.

Often confused with reactive intermediates, in chemistry, a reaction intermediate is a molecular entity formed momentarily in a multi-step reaction. This intermediate emerges from initial reactants and/or preceding intermediates but is consumed in a subsequent step, thus not appearing in the final chemical equation.

Consider, for instance, this hypothetical reaction:

A + B → C + D

If the reaction involves these two elementary steps:

A + B → X

X → C + D

then X is designated as a reaction intermediate.

The term reaction intermediate is often abbreviated to intermediate, a preference by IUPAC. However, this term can also denote reactive intermediates and chemicals like cumene, which are significant within the chemical industry but not in everyday commerce.

The IUPAC Gold Book describes an intermediate as a compound with a lifespan longer than molecular vibrations, formed directly or indirectly from reactants, and further reacting to produce final chemicals. This definition differentiates true intermediates from transient vibrational and transition states.

The rate of forming and consuming intermediates can vary significantly among multi-step reactions. An intermediate that reacts swiftly compared to another might be termed a relative intermediate. Reactive intermediates, characterized by their brief existence, are usually high-energy, unstable, and challenging to isolate.

Carbocations, positively-charged carbon ions, are crucial in synthesizing various compounds.

Carbocation Intermediates in Alkene Addition Reactions

In HX addition reactions, an alkene's pi bond acts as a nucleophile, bonding with a proton from an HX molecule (where X is a halogen), forming a carbocation intermediate.

CH2CH2 + HX → CH2CH⁺3 + X⁻

CH2CH⁺3 + X⁻ → CH2XCH3

Carbocation Intermediates in Nucleophilic Substitution Reactions

In SN1 reactions, a leaving group detaches from a molecule forming a carbocation intermediate, which a nucleophile then attacks to create the final product, such as in 2-bromo-2-methylpropane converting to 2-methyl-2-propanol.

(CH3)3CBr → (CH3)3C⁺

(CH3)3C⁺ + H2O → (CH3)3OH²⁺

(CH3)3OH²⁺ → (CH3)3OH + H⁺

Carbocation Intermediates in Elimination Reactions

In E1 elimination reactions, a leaving group removes itself creating a carbocation intermediate. A solvent then removes a proton from a nearby carbon leading to the formation of a pi bond.

Carbanions, organic molecules with a negatively charged carbon atom, are potent nucleophiles utilized to extend carbon backbones in synthesis reactions. For instance:

C2H2 reacts with NaNH2 in NH3(l) → CHC⁻

CHC⁻ + BrCH2CH3 → CHC⁻CH2CH3

This example illustrates the role of carbanion intermediates in reaction sequences.

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Radicals, species with unpaired electrons, exhibit high reactivity and short lifespans. They engage in hydrogen abstraction from carbon-containing molecules, initiating propagation chains to form stable products.

Methane Chlorination: A Radical Chain Reaction

The methane chlorination reaction demonstrates a chain process involving radicals and several intermediate species:

CH4 + Cl2 → CH3Cl + HCl

CH3Cl + Cl2 → CH2Cl2 + HCl

CH2Cl2 + Cl2 → CHCl3 + HCl

CHCl3 + Cl2 → CCl4 + HCl

These steps involve radical intermediates like CH3Cl, CH2Cl2, and CHCl3, integral to the overall reaction.

Intermediates play crucial roles in biological processes. For example, metallo-β-lactamase, an enzyme providing antibiotic resistance, forms intermediates utilizing zinc in its catalytic pathway. Another protein, AAA-ATPase p97, linked to diseases and cancer, involves an ADP.Pi nucleotide intermediate in its function.

Similarly, RCL enzymes catalyzing glycosidic bonds rely on intermediates during methanolysis reactions.

In the industrial sector, intermediates are often stable reaction products valuable primarily as precursor chemicals. A quintessential instance is cumene, produced from benzene and propylene, and chiefly used to manufacture acetone and phenol. Although cumene itself holds limited intrinsic value, its derivatives are essential across various industries.

What is the significance of controlling conditions for intermediates?

Strictly controlled conditions for intermediates are imperative to reduce human and environmental exposure. For transported isolated intermediates, regulatory compliance ensures these compounds do not pose hazards during transit or storage.

How are intermediates utilized in pharmaceutical production?

Pharmaceutical industries frequently deploy intermediates to streamline multi-step syntheses of complex drugs. These intermediates often structurally resemble final products, facilitating short and efficient synthesis pathways.

Why are reactive intermediates challenging to isolate?

Reactive intermediates are inherently unstable with fleeting lifespans, making isolation and study difficult. Advanced techniques like spectroscopy and cryogenic trapping aid in observing these intermediates within controlled environments.