Reaction intermediate

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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]

Contents

For example, consider this hypothetical reaction:

A + B → C + D

If this overall reaction comprises two elementary steps thus:

A + B → X
X → C + D

then X is a reaction intermediate.

The phrase reaction intermediate is 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 → CH2CH+3 + X−
CH2CH+3 + 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]+ → CH2CH+3 + H2O
CH2CH+3 + H2O → CH2OH2CH+3
CH2OH2CH+3 + H2O → CH3CH2OH + [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. SN1 and SN2 are two different mechanisms for nucleophilic substitution, and SN1 involves a carbocation intermediate. In SN1, 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)3OH+2
(CH3)3OH+2 → (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]

E1 elimination reaction.png
C2H2 with NaNH2 in NH3(l) → CHC−
CHC− + BrCH2CH3 → CHC−CH2CH3

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 to 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:

CH4 + 4 Cl2 → CCl4 + 4 HCl

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 is called a chain reaction. Following only the carbon containing species in series:

CH4 → CH3Cl → CH2Cl2 → CHCl3 → CCl4

Reactants: CH4 + 4 Cl2

Products: CCl4 + 4 HCl

The other species are reaction intermediates: CH3Cl, CH2Cl2, CHCl3

These are the set of irreversible second-order reactions:

CH4 + Cl2 → CH3Cl + HCl
CH3Cl + Cl2 → CH2Cl2 + HCl
CH2Cl2 + Cl2 → CHCl3 + HCl
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.

Cl−Clhν→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.

CH3−H + Cl• → CH3• + H−Cl
CH2Cl−H + Cl• → CH2Cl• + H−Cl
CHCl2−H + Cl• → CHCl2• + H−Cl
CCl3−H + Cl• → CCl3• + H−Cl

These new radical carbon containing species now react with a second CHCCl2 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.

CH3• + Cl−Cl → CH3Cl + Cl•
CH2Cl• + Cl−Cl → CH2Cl2 + Cl•
CHCl2• + Cl−Cl → CHCl3 + Cl•
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).

CH3• + CH3• → CH3−CH3

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

CH3• + Cl• → CH3Cl

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

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.Pi 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]

See also

Related Research Articles

<span class="mw-page-title-main">Chlorine</span> Chemical element with atomic number 17 (Cl)

Chlorine is a chemical element; it has symbol Cl and atomic number 17. The second-lightest of the halogens, it appears between fluorine and bromine in the periodic table and its properties are mostly intermediate between them. Chlorine is a yellow-green gas at room temperature. It is an extremely reactive element and a strong oxidising agent: among the elements, it has the highest electron affinity and the third-highest electronegativity on the revised Pauling scale, behind only oxygen and fluorine.

<span class="mw-page-title-main">Carboxylic acid</span> Organic compound containing a –C(=O)OH group

In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group attached to an R-group. The general formula of a carboxylic acid is often written as R−COOH or R−CO2H, sometimes as R−C(O)OH with R referring to an organyl group, or hydrogen, or other groups. Carboxylic acids occur widely. Important examples include the amino acids and fatty acids. Deprotonation of a carboxylic acid gives a carboxylate anion.

<span class="mw-page-title-main">Chemical reaction</span> Process that results in the interconversion of chemical species

A chemical reaction is a process that leads to the chemical transformation of one set of chemical substances to another. When chemical reactions occur, the atoms are rearranged and the reaction is accompanied by an energy change as new products are generated. Classically, chemical reactions encompass changes that only involve the positions of electrons in the forming and breaking of chemical bonds between atoms, with no change to the nuclei, and can often be described by a chemical equation. Nuclear chemistry is a sub-discipline of chemistry that involves the chemical reactions of unstable and radioactive elements where both electronic and nuclear changes can occur.

Chloroform, or trichloromethane, is an organochloride with the formula CHCl3 and a common solvent. It is a very volatile, colorless, strong-smelling, dense liquid produced on a large scale as a precursor to refrigerants and PTFE. Chloroform is a trihalomethane that serves as a powerful general anesthetic, euphoriant, anxiolytic, and sedative when inhaled or ingested, for this reason, Chloroform was used as an inhalational anesthetic between the 19th century and the first half of the 20th century. It is miscible with many solvents but it is only very slightly soluble in water.

The compound hydrogen chloride has the chemical formula HCl and as such is a hydrogen halide. At room temperature, it is a colorless gas, which forms white fumes of hydrochloric acid upon contact with atmospheric water vapor. Hydrogen chloride gas and hydrochloric acid are important in technology and industry. Hydrochloric acid, the aqueous solution of hydrogen chloride, is also commonly given the formula HCl.

A halogen addition reaction is a simple organic reaction where a halogen molecule is added to the carbon–carbon double bond of an alkene functional group.

<span class="mw-page-title-main">Leaving group</span> Atom(s) which detach from the substrate during a chemical reaction

In chemistry, a leaving group is defined by the IUPAC as an atom or group of atoms that detaches from the main or residual part of a substrate during a reaction or elementary step of a reaction. However, in common usage, the term is often limited to a fragment that departs with a pair of electrons in heterolytic bond cleavage. In this usage, a leaving group is a less formal but more commonly used synonym of the term nucleofuge. In this context, leaving groups are generally anions or neutral species, departing from neutral or cationic substrates, respectively, though in rare cases, cations leaving from a dicationic substrate are also known.

Chloromethane, also called methyl chloride, Refrigerant-40, R-40 or HCC 40, is an organic compound with the chemical formula CH3Cl. One of the haloalkanes, it is a colorless, sweet-smelling, flammable gas. Methyl chloride is a crucial reagent in industrial chemistry, although it is rarely present in consumer products, and was formerly utilized as a refrigerant. Most chloromethane is biogenic.

In chemistry, an electrophile is a chemical species that forms bonds with nucleophiles by accepting an electron pair. Because electrophiles accept electrons, they are Lewis acids. Most electrophiles are positively charged, have an atom that carries a partial positive charge, or have an atom that does not have an octet of electrons.

A substitution reaction is a chemical reaction during which one functional group in a chemical compound is replaced by another functional group. Substitution reactions are of prime importance in organic chemistry. Substitution reactions in organic chemistry are classified either as electrophilic or nucleophilic depending upon the reagent involved, whether a reactive intermediate involved in the reaction is a carbocation, a carbanion or a free radical, and whether the substrate is aliphatic or aromatic. Detailed understanding of a reaction type helps to predict the product outcome in a reaction. It also is helpful for optimizing a reaction with regard to variables such as temperature and choice of solvent.

In chemistry, halogenation is a chemical reaction which introduces one or more halogens into a chemical compound. Halide-containing compounds are pervasive, making this type of transformation important, e.g. in the production of polymers, drugs. This kind of conversion is in fact so common that a comprehensive overview is challenging. This article mainly deals with halogenation using elemental halogens. Halides are also commonly introduced using salts of the halides and halogen acids. Many specialized reagents exist for and introducing halogens into diverse substrates, e.g. thionyl chloride.

<span class="mw-page-title-main">Halomethane</span> Halogen compounds derived from methane

Halomethane compounds are derivatives of methane with one or more of the hydrogen atoms replaced with halogen atoms. Halomethanes are both naturally occurring, especially in marine environments, and human-made, most notably as refrigerants, solvents, propellants, and fumigants. Many, including the chlorofluorocarbons, have attracted wide attention because they become active when exposed to ultraviolet light found at high altitudes and destroy the Earth's protective ozone layer.

In organic chemistry, free-radical halogenation is a type of halogenation. This chemical reaction is typical of alkanes and alkyl-substituted aromatics under application of UV light. The reaction is used for the industrial synthesis of chloroform (CHCl3), dichloromethane (CH2Cl2), and hexachlorobutadiene. It proceeds by a free-radical chain mechanism.

In chemical kinetics, the overall rate of a reaction is often approximately determined by the slowest step, known as the rate-determining step or rate-limiting step. For a given reaction mechanism, the prediction of the corresponding rate equation is often simplified by using this approximation of the rate-determining step.

In inorganic chemistry, chlorosilanes are a group of reactive, chlorine-containing chemical compounds, related to silane and used in many chemical processes. Each such chemical has at least one silicon-chlorine bond. Trichlorosilane is produced on the largest scale. The parent chlorosilane is silicon tetrachloride.

A salt metathesis reaction is a chemical process involving the exchange of bonds between two reacting chemical species which results in the creation of products with similar or identical bonding affiliations. This reaction is represented by the general scheme:

<span class="mw-page-title-main">Sulfuryl chloride</span> Chemical compound

Sulfuryl chloride is an inorganic compound with the formula SO2Cl2. At room temperature, it is a colorless liquid with a pungent odor. Sulfuryl chloride is not found in nature, as can be inferred from its rapid hydrolysis.

<span class="mw-page-title-main">Carbenium ion</span> Class of ions

A carbenium ion is a positive ion with the structure RR′R″C+, that is, a chemical species with carbon atom having three covalent bonds, and it bears a +1 formal charge. But IUPAC confuses coordination number with valence, incorrectly considering carbon in carbenium as trivalent.

Chain propagation (sometimes referred to as propagation) is a process in which a reactive intermediate is continuously regenerated during the course of a chemical chain reaction. For example, in the chlorination of methane, there is a two-step propagation cycle involving as chain carriers a chlorine atom and a methyl radical which are regenerated alternately:

<span class="mw-page-title-main">Vanadium oxytrichloride</span> Chemical compound

Vanadium oxytrichloride is the inorganic compound with the formula VOCl3. This yellow distillable liquid hydrolyzes readily in air. It is an oxidizing agent. It is used as a reagent in organic synthesis. Samples often appear red or orange owing to an impurity of vanadium tetrachloride.

References

  1. ↑ Moore, John W. (2015). Chemistry : the molecular science. Conrad L. Stanitski (Fifth ed.). Stamford, CT. ISBN   978-1-285-19904-7. OCLC   891494431.{{cite book}}: CS1 maint: location missing publisher (link)
  2. ↑ Chemistry (IUPAC), The International Union of Pure and Applied. "IUPAC - intermediate (I03096)". goldbook.iupac.org. Retrieved 2023-09-22.
  3. ↑ Chemistry (IUPAC), The International Union of Pure and Applied. "IUPAC - intermediate (I03096)". goldbook.iupac.org. Retrieved 2022-11-17.
  4. 1 2 3 4 5 6 Brown, William Henry (2018). Organic chemistry. Brent L. Iverson, Eric V. Anslyn, Christopher S. Foote (Eighth ed.). Boston, MA. ISBN   978-1-305-58035-0. OCLC   974377227.{{cite book}}: CS1 maint: location missing publisher (link)
  5. ↑ Ouellette, Robert J. (2014). Organic Chemistry : Structure, Mechanism, and Synthesis. J. David Rawn. [Place of publication not identified]: Elsevier. ISBN   978-1-306-87645-2. OCLC   881509857.
  6. ↑ Garrity, James D.; Bennett, Brian; Crowder, Michael W. (2005-01-01). "Direct Evidence That the Reaction Intermediate of Metallo-β-lactamase L1 Is Metal Bound". Biochemistry. 44 (3): 1078–1087. doi:10.1021/bi048385b. ISSN   0006-2960. PMID   15654764. S2CID   10042904.
  7. ↑ Rydzek, Simon; Shein, Mikhail; Bielytskyi, Pavlo; Schütz, Anne K. (2020-08-26). "Observation of a Transient Reaction Intermediate Illuminates the Mechanochemical Cycle of the AAA-ATPase p97". Journal of the American Chemical Society. 142 (34): 14472–14480. doi:10.1021/jacs.0c03180. ISSN   0002-7863. S2CID   221123424.
  8. ↑ Doddapaneni, Kiran; Zahurancik, Walter; Haushalter, Adam; Yuan, Chunhua; Jackman, Jane; Wu, Zhengrong (2011-05-31). "RCL Hydrolyzes 2′-Deoxyribonucleoside 5′-Monophosphate via Formation of a Reaction Intermediate". Biochemistry. 50 (21): 4712–4719. doi:10.1021/bi101742z. ISSN   0006-2960. PMID   21510673.
  9. ↑ Some Chemicals Present in Industrial and Consumer Products, Food and Drinking-Water. Lyon (FR): International Agency for Research on Cancer. 2013. ISBN   978-9283213246.
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