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In
chemistry Chemistry is the scientific study of the properties and behavior of matter. It is a natural science that covers the elements that make up matter to the compounds made of atoms, molecules and ions: their composition, structure, proper ...
, a nucleophilic substitution is a class of
chemical reaction A chemical reaction is a process that leads to the chemical transformation of one set of chemical substances to another. Classically, chemical reactions encompass changes that only involve the positions of electrons in the forming and breaking ...
s in which an
electron The electron ( or ) is a subatomic particle with a negative one elementary electric charge. Electrons belong to the first generation of the lepton particle family, and are generally thought to be elementary particles because they have n ...
-rich
chemical species A chemical species is a chemical substance or ensemble composed of chemically identical molecular entities that can explore the same set of molecular energy levels on a characteristic or delineated time scale. These energy levels determine the wa ...
(known as a
nucleophile In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they ar ...
) replaces a
functional group In organic chemistry, a functional group is a substituent or moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions regardless of the r ...
within another electron-deficient molecule (known as the electrophile). The molecule that contains the electrophile and the leaving functional group is called the substrate. The most general form of the reaction may be given as the following: :\text\mathbf + \ce + \text\mathbf The electron pair (:) from the nucleophile (Nuc) attacks the substrate () and bonds with it. Simultaneously, the leaving group (LG) departs with an electron pair. The principal product in this case is . The nucleophile may be electrically neutral or negatively charged, whereas the substrate is typically neutral or positively charged. An example of nucleophilic substitution is the
hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile. Biological hydrolysi ...
of an
alkyl In organic chemistry, an alkyl group is an alkane missing one hydrogen. The term ''alkyl'' is intentionally unspecific to include many possible substitutions. An acyclic alkyl has the general formula of . A cycloalkyl is derived from a cycloa ...
bromide A bromide ion is the negatively charged form (Br−) of the element bromine, a member of the halogens group on the periodic table. Most bromides are colorless. Bromides have many practical roles, being found in anticonvulsants, flame-retardant ...
, R-Br under basic conditions, where the attacking nucleophile is
hydroxyl In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydrox ...
() and the
leaving group 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 ...
is
bromide A bromide ion is the negatively charged form (Br−) of the element bromine, a member of the halogens group on the periodic table. Most bromides are colorless. Bromides have many practical roles, being found in anticonvulsants, flame-retardant ...
(). :R-Br + OH- -> R-OH + Br- Nucleophilic substitution reactions are common in
organic chemistry Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, and reactions of organic compounds and organic materials, i.e., matter in its various forms that contain carbon atoms.Clayden, J ...
. Nucleophiles often attack a saturated
aliphatic In organic chemistry, hydrocarbons ( compounds composed solely of carbon and hydrogen) are divided into two classes: aromatic compounds and aliphatic compounds (; G. ''aleiphar'', fat, oil). Aliphatic compounds can be saturated, like hexane ...
carbon. Less often, they may attack an
aromatic In chemistry, aromaticity is a chemical property of cyclic ( ring-shaped), ''typically'' planar (flat) molecular structures with pi bonds in resonance (those containing delocalized electrons) that gives increased stability compared to satur ...
or unsaturated carbon. Very important reaction


Saturated carbon centres


SN1 and SN2 reactions

In 1935, Edward D. Hughes and Sir Christopher Ingold studied nucleophilic substitution reactions of
alkyl halide The haloalkanes (also known as halogenoalkanes or alkyl halides) are alkanes containing one or more halogen substituents. They are a subset of the general class of halocarbons, although the distinction is not often made. Haloalkanes are widely us ...
s and related compounds. They proposed that there were two main mechanisms at work, both of them competing with each other. The two main mechanisms were the SN1 reaction and the SN2 reaction, where ''S'' stands for substitution, ''N'' stands for nucleophilic, and the number represents the kinetic order of the reaction. In the SN2 reaction, the addition of the nucleophile and the elimination of leaving group take place simultaneously (i.e. a concerted reaction). SN2 occurs when the central carbon atom is easily accessible to the nucleophile. In SN2 reactions, there are a few conditions that affect the rate of the reaction. First of all, the 2 in SN2 implies that there are two concentrations of substances that affect the rate of reaction: substrate (Sub) and nucleophile. The rate equation for this reaction would be Rate=k ubNuc]. For a SN2 reaction, an Protic_solvent, aprotic solvent is best, such as acetone, DMF, or DMSO. Aprotic solvents do not add protons (H+ ions) into solution; if protons were present in SN2 reactions, they would react with the nucleophile and severely limit the reaction rate. Since this reaction occurs in one step,
steric effects Steric effects arise from the spatial arrangement of atoms. When atoms come close together there is a rise in the energy of the molecule. Steric effects are nonbonding interactions that influence the shape ( conformation) and reactivity of ions ...
drive the reaction speed. In the intermediate step, the nucleophile is 185 degrees from the leaving group and the stereochemistry is inverted as the nucleophile bonds to make the product. Also, because the intermediate is partially bonded to the nucleophile and leaving group, there is no time for the substrate to rearrange itself: the nucleophile will bond to the same carbon that the leaving group was attached to. A final factor that affects reaction rate is nucleophilicity; the nucleophile must attack an atom other than a hydrogen. By contrast the SN1 reaction involves two steps. SN1 reactions tend to be important when the central carbon atom of the substrate is surrounded by bulky groups, both because such groups interfere sterically with the SN2 reaction (discussed above) and because a highly substituted carbon forms a stable
carbocation A carbocation is an ion with a positively charged carbon atom. Among the simplest examples are the methenium , methanium and vinyl cations. Occasionally, carbocations that bear more than one positively charged carbon atom are also encount ...
. Like SN2 reactions, there are quite a few factors that affect the reaction rate of SN1 reactions. Instead of having two concentrations that affect the reaction rate, there is only one, substrate. The rate equation for this would be Rate=k ub Since the rate of a reaction is only determined by its slowest step, the rate at which the leaving group "leaves" determines the speed of the reaction. This means that the better the leaving group, the faster the reaction rate. A general rule for what makes a good leaving group is the weaker the conjugate base, the better the leaving group. In this case, halogens are going to be the best leaving groups, while compounds such as amines, hydrogen, and alkanes are going to be quite poor leaving groups. As SN2 reactions were affected by sterics, SN1 reactions are determined by bulky groups attached to the carbocation. Since there is an intermediate that actually contains a positive charge, bulky groups attached are going to help stabilize the charge on the carbocation through resonance and distribution of charge. In this case, tertiary carbocation will react faster than a secondary which will react much faster than a primary. It is also due to this carbocation intermediate that the product does not have to have inversion. The nucleophile can attack from the top or the bottom and therefore create a racemic product. It is important to use a protic solvent, water and alcohols, since an aprotic solvent could attack the intermediate and cause unwanted product. It does not matter if the hydrogens from the protic solvent react with the nucleophile since the nucleophile is not involved in the rate determining step.


Reactions

There are many reactions in organic chemistry involve this type of mechanism. Common examples include: *
Organic reduction Organic reductions or organic oxidations or organic redox reactions are redox reactions that take place with organic compounds. In organic chemistry oxidations and reductions are different from ordinary redox reactions, because many reactions carr ...
s with
hydride In chemistry, a hydride is formally the anion of hydrogen( H−). The term is applied loosely. At one extreme, all compounds containing covalently bound H atoms are called hydrides: water (H2O) is a hydride of oxygen, ammonia is a hydride ...
s, for example :: using   (S2) *
Hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile. Biological hydrolysi ...
reactions such as :: (S2) or ::   (S1) *
Williamson ether synthesis The Williamson ether synthesis is an organic reaction, forming an ether from an organohalide and a deprotonated alcohol (alkoxide). This reaction was developed by Alexander Williamson in 1850. Typically it involves the reaction of an alkoxide io ...
::   (S2) * The Wenker synthesis, a ring-closing reaction of aminoalcohols. * The Finkelstein reaction, a halide exchange reaction. Phosphorus nucleophiles appear in the Perkow reaction and the Michaelis–Arbuzov reaction. * The Kolbe nitrile synthesis, the reaction of alkyl halides with cyanides.


Borderline mechanism

An example of a substitution reaction taking place by a so-called borderline mechanism as originally studied by Hughes and Ingold is the reaction of ''1-phenylethyl chloride'' with sodium methoxide in methanol. : The
reaction rate The reaction rate or rate of reaction is the speed at which a chemical reaction takes place, defined as proportional to the increase in the concentration of a product per unit time and to the decrease in the concentration of a reactant per uni ...
is found to the sum of S1 and S2 components with 61% (3,5 M, 70 °C) taking place by the latter.


Other mechanisms

Besides S1 and S2, other mechanisms are known, although they are less common. The Si mechanism is observed in reactions of thionyl chloride with
alcohol Alcohol most commonly refers to: * Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom * Alcohol (drug), an intoxicant found in alcoholic drinks Alcohol may also refer to: Chemicals * Ethanol, one of sev ...
s, and it is similar to S1 except that the nucleophile is delivered from the same side as the leaving group. Nucleophilic substitutions can be accompanied by an
allylic rearrangement An allylic rearrangement or allylic shift is an organic reaction in which the double bond in an allyl chemical compound shifts to the next carbon atom. It is encountered in nucleophilic substitution. In reaction conditions that favor a SN1 react ...
as seen in reactions such as the Ferrier rearrangement. This type of mechanism is called an S1' or S2' reaction (depending on the kinetics). With
allyl In organic chemistry, an allyl group is a substituent with the structural formula , where R is the rest of the molecule. It consists of a methylene bridge () attached to a vinyl group (). The name is derived from the scientific name for garlic, ...
ic halides or sulphonates, for example, the nucleophile may attack at the γ unsaturated carbon in place of the carbon bearing the leaving group. This may be seen in the reaction of 1-chloro-2-butene with
sodium hydroxide Sodium hydroxide, also known as lye and caustic soda, is an inorganic compound with the formula NaOH. It is a white solid ionic compound consisting of sodium cations and hydroxide anions . Sodium hydroxide is a highly caustic base and al ...
to give a mixture of 2-buten-1-ol and 1-buten-3-ol: :CH3CH=CH-CH2-Cl -> CH3CH=CH-CH2-OH + CH3CH(OH)-CH=CH2 The Sn1CB mechanism appears in
inorganic chemistry Inorganic chemistry deals with synthesis and behavior of inorganic and organometallic compounds. This field covers chemical compounds that are not carbon-based, which are the subjects of organic chemistry. The distinction between the two disci ...
. Competing mechanisms exist.Unimolecular Nucleophilic Substitution does not Exist! / N.S.Imyanitov
SciTecLibrary
/ref> In
organometallic chemistry Organometallic chemistry is the study of organometallic compounds, chemical compounds containing at least one chemical bond between a carbon atom of an organic molecule and a metal, including alkali, alkaline earth, and transition metals, and s ...
the nucleophilic abstraction reaction occurs with a nucleophilic substitution mechanism.


Unsaturated carbon centres

Nucleophilic substitution via the SN1 or SN2 mechanism does not generally occur with vinyl or aryl halides or related compounds. Under certain conditions nucleophilic substitutions may occur, via other mechanisms such as those described in the
nucleophilic aromatic substitution A nucleophilic aromatic substitution is a substitution reaction in organic chemistry in which the nucleophile displaces a good leaving group, such as a halide, on an aromatic ring. Aromatic rings are usually nucleophilic, but some aromatic compou ...
article. When the substitution occurs at the
carbonyl In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups. A compound containi ...
group, the
acyl In chemistry, an acyl group is a moiety derived by the removal of one or more hydroxyl groups from an oxoacid, including inorganic acids. It contains a double-bonded oxygen atom and an alkyl group (). In organic chemistry, the acyl group (IUPAC ...
group may undergo nucleophilic acyl substitution. This is the normal mode of substitution with
carboxylic acid 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 or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxyli ...
derivatives such as
acyl chloride In organic chemistry, an acyl chloride (or acid chloride) is an organic compound with the functional group . Their formula is usually written , where R is a side chain. They are reactive derivatives of carboxylic acids (). A specific example o ...
s,
ester In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ...
s and
amide In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it i ...
s.


References


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