Alkylation is the transfer of an alkyl group from one molecule to
another. The alkyl group may be transferred as an alkyl carbocation, a
free radical, a carbanion or a carbene (or their equivalents). An
alkyl group is a piece of a molecule with the general formula CnH2n+1,
where n is the integer depicting the number of carbons linked
together. For example, a methyl group (n = 1, CH3) is a
fragment of a methane molecule (CH4). Alkylating agents utilize
selective alkylation by adding the desired aliphatic carbon chain to
the previously chosen starting molecule. This is one of many known
Alkyl groups can also be removed in a process
known as dealkylation.
In oil refining contexts, alkylation refers to a particular alkylation
of isobutane with olefins. For upgrading of petroleum, alkylation
produces synthetic C7–C8[further explanation needed] alkylate, which
is a premium blending stock for gasoline.
In medicine, alkylation of
DNA is used in chemotherapy to damage the
DNA of cancer cells.
Alkylation is accomplished with the class of
drugs called alkylating antineoplastic agents.
1 Alkylating agents
Nucleophilic alkylating agents
Electrophilic alkylating agents
Carbene alkylating agents
3 In biology
4 Oil refining
5 See also
7 External links
Alkylating agents are classified according to their nucleophilic or
Nucleophilic alkylating agents
Nucleophilic alkylating agents deliver the equivalent of an alkyl
anion (carbanion). Examples include the use of organometallic
compounds such as Grignard (organomagnesium), organolithium,
organocopper, and organosodium reagents. These compounds typically can
add to an electron-deficient carbon atom such as at a carbonyl group.
Nucleophilic alkylating agents can also displace halide substituents
on a carbon atom. In the presence of catalysts, they also alkylate
alkyl and aryl halides, as exemplified by Suzuki couplings.
Electrophilic alkylating agents
Electrophilic alkylating agents deliver the equivalent of an alkyl
cation. Examples include the use of alkyl halides with a Lewis acid
catalyst to alkylate aromatic substrates in
Alkyl halides can also react directly with amines to form C-N bonds;
the same holds true for other nucleophiles such as alcohols,
carboxylic acids, thiols, etc.
Trimethyloxonium tetrafluoroborate and
triethyloxonium tetrafluoroborate are particularly strong
electrophiles due to their overt positive charge and an inert leaving
group (dimethyl or diethyl ether).
Electrophilic, soluble alkylating agents are often very toxic, due to
their ability to alkylate DNA. They should be handled with proper PPE.
This mechanism of toxicity is also responsible for the ability of some
alkylating agents to perform as anti-cancer drugs in the form of
alkylating antineoplastic agents, and also as chemical weapons such as
mustard gas. Alkylated
DNA either does not coil or uncoil properly, or
cannot be processed by information-decoding enzymes. This results in
cytotoxicity with the effects of inhibition the growth of the cell,
initiation of programmed cell death or apoptosis. However, mutations
are also triggered, including carcinogenic mutations, explaining the
higher incidence of cancer after exposure.
Alcohols and phenols can be alkylated to give alkyl ethers:
displaystyle mathrm R - OH + R' - X longrightarrow R - O - R' +
H - X
The produced acid HX is neutralized with a base, or, alternatively,
the alcohol is deprotonated first to give an alkoxide or phenoxide.
For example, dimethyl sulfate alkylates the sodium salt of phenol to
give anisole, the methyl ether of phenol. The dimethyl sulfate is
dealkylated to sodium methylsulfate.
displaystyle mathrm Ph - O^ - + Me_ 2 - SO_ 4 longrightarrow
Ph - O - Me + Me - SO_ 4 ^ -
(with Na+ as a spectator ion)
On the contrary, the alkylation of amines introduces the problem that
the alkylation of an amine makes it more nucleophilic. Thus, when an
electrophilic alkylating agent is introduced to a primary amine, it
will preferentially alkylate all the way to a quaternary ammonium
displaystyle mathrm R - NH_ 2 + R - NH - R' longrightarrow R -
N(R')_ 2 longrightarrow R - N(R')_ 3 ^ +
(alkylating agent omitted for clarity)
If the quaternary ammonium is not the desired product, more circuitous
routes such as reductive amination are necessary.
Carbene alkylating agents
Carbenes are extremely reactive and are known to attack even
unactivated C-H bonds. Carbenes can be generated by elimination of a
diazo group. Unlike electrophilic or nucleophilic alkylating agents,
carbenes are neutral, and they insert into bonds rather than discard
leaving groups. A metal can form a carbene equivalent called a
transition metal carbene complex.
Silicotungstic acid is used to manufacture ethyl acetate by the
alkylation of acetic acid by ethylene:
C2H4 + CH3CO2H → CH3CO2C2H5
It has also been commercialized for the oxidation of ethylene to
C2H4 + O2 → CH3CO2H
Main article: methylation
Methylation is the most common type of alkylation, being associated
with the transfer of a methyl group.
Methylation is distinct from
alkylation in that it is specifically the transfer of one carbon,
whereas alkylation can refer to the transfer of long chain carbon
Methylation in nature is typically effected by vitamin
B12-derived enzymes, where the methyl group is carried by cobalt. In
methanogenesis, coenzyme M is methylated by tetrahydromethanopterin.
Electrophilic compounds may alkylate different nucleophiles in the
body. The toxicity, carcinogenity, and paradoxically, cancer
cell-killing abilities of different
DNA alkylating agents are an
Demethylation is the reverse of methylation.
Main article: alkylation unit
Alkylation of alkenes (shown in red is propene) by isobutane is a
major process in refineries to produce higher octane "alkylate" for
gasoline blending, in this example yielding isoheptane. It is
catalysed by strong acids such as hydrofluoric acid (HF) and sulfuric
In a standard oil refinery process, isobutane is alkylated with
low-molecular-weight alkenes (primarily a mixture of propene and
butene) in the presence of a Bronsted acid catalyst, either sulfuric
acid or hydrofluoric acid. In an oil refinery it is referred to as
a sulfuric acid alkylation unit (SAAU) or a hydrofluoric alkylation
unit, (HFAU). Refinery workers may simply refer to it as the alky or
alky unit. The catalyst protonates the alkenes (propene, butene) to
produce reactive carbocations, which alkylate isobutane. The reaction
is carried out at mild temperatures (0 and 30 °C) in a two-phase
reaction. Because the reaction is exothermic, cooling is needed: SAAU
plants require lower temperatures so the cooling medium needs to be
chilled, for HFAU normal refinery cooling water will suffice. It is
important to keep a high ratio of isobutane to alkene at the point of
reaction to prevent side reactions which produces a lower octane
product, so the plants have a high recycle of isobutane back to feed.
The phases separate spontaneously, so the acid phase is vigorously
mixed with the hydrocarbon phase to create sufficient contact surface.
The product is called alkylate and is composed of a mixture of
high-octane, branched-chain paraffinic hydrocarbons (mostly isoheptane
and isooctane). Alkylate is a premium gasoline blending stock because
it has exceptional antiknock properties and is clean burning. Alkylate
is also a key component of avgas. The octane number of the alkylate
depends mainly upon the kind of alkenes used and upon operating
conditions. For example, isooctane results from combining butylene
with isobutane and has an octane rating of 100 by definition. There
are other products in the alkylate, so the octane rating will vary
Since crude oil generally contains only 10 to 40 percent of
hydrocarbon constituents in the gasoline range, refineries use a fluid
catalytic cracking process to convert high molecular weight
hydrocarbons into smaller and more volatile compounds, which are then
converted into liquid gasoline-size hydrocarbons.
transform low molecular-weight alkenes and iso-paraffin molecules into
larger iso-paraffins with a high octane number.
Combining cracking, polymerization, and alkylation can result in a
gasoline yield representing 70 percent of the starting crude oil. More
advanced processes, such as cyclicization of paraffins and
dehydrogenation of naphthenes forming aromatic hydrocarbons in a
catalytic reformer, have also been developed to increase the octane
rating of gasoline. Modern refinery operation can be shifted to
produce almost any fuel type with specified performance criteria from
a single crude feedstock.
Refineries examine whether it makes sense economically to install
Alkylation units are complex, with substantial
economy of scale. In addition to a suitable quantity of feedstock, the
price spread between the value of alkylate product and alternate
feedstock disposition value must be large enough to justify the
installation. Alternative outlets for refinery alklylation feedstocks
include sales as LPG, blending of C4 streams directly into gasoline to
lower the flash point of the product and feedstocks for chemical
plants. Local market conditions vary widely between plants. Variation
in the RVP (Reid vapor pressure) specification for gasoline between
countries and between seasons dramatically impacts the amount of
butane streams that can be blended directly into gasoline. The
transportation of specific types of LPG streams can be expensive so
local disparities in economic conditions are often not fully mitigated
by cross market movements[further explanation needed] of alkylation
The availability of a suitable catalyst is also an important factor in
deciding whether to build an alkylation plant. If sulfuric acid is
used, significant volumes are needed. Access to a suitable plant is
required for the supply of fresh acid and the disposition of spent
acid. If a sulfuric acid plant must be constructed specifically to
support an alkylation unit, such construction will have a significant
impact on both the initial requirements for capital and ongoing costs
of operation. Alternatively it is possible to install a WSA Process
unit to regenerate the spent acid. No drying of the gas takes place.
This means that there will be no loss of acid, no acidic waste
material and no heat is lost in process gas reheating. The selective
condensation in the WSA condenser ensures that the regenerated fresh
acid will be 98% w/w even with the humid process gas. It is possible
to combine spent acid regeneration with disposal of hydrogen sulfide
by using the hydrogen sulfide as internal fuel in the refinery or
The second main catalyst option is hydrofluoric acid. In typical
alkylation plants, rates of consumption for acid are much lower than
for sulfuric acid. These plants also produce alkylate with better
octane rating than do sulfuric plants. However, due to its hazardous
nature, HF acid is produced at very few locations and transportation
must be managed rigorously.
^ March Jerry; (1985). Advanced Organic Chemistry reactions,
mechanisms and structure (3rd ed.). New York: John Wiley & Sons,
inc. ISBN 0-471-85472-7
^ Stefanidakis, G.; Gwyn, J.E. (1993). "Alkylation". In John J.
McKetta. Chemical Processing Handbook. CRC Press. pp. 80–138.
^ G. S. Hiers and F. D. Hager (1941). "Anisole". Organic
Syntheses. ; Collective Volume, 1, p. 58
^ Misono, Makoto (2009). "Recent progress in the practical
applications of heteropolyacid and perovskite catalysts: Catalytic
technology for the sustainable society". Catalysis Today. 144 (3-4):
^ Michael Röper, Eugen Gehrer, Thomas Narbeshuber, Wolfgang Siegel
"Acylation and Alkylation" in Ullmann's Encyclopedia of Industrial
Chemistry, Wiley-VCH, Weinheim, 2000. doi:10.1002/14356007.a01_185
^ Sulphur recovery; (2007). The Process Principles, details advances
in sulphur recovery by the WSA process. Denmark: Jens Kristen Laursen,
Haldor Topsøe A/S. Reprinted from Hydrocarbonengineering August 2007
Macrogalleria page on polycarbonate production
Alkylating agents at the US National Library of Medicine Medical
Subject Headings (MeSH)