The nucleophilic substitution is a type of reaction in organic chemistry . Here, reacts a nucleophile in the form of a Lewis base ( electron pair donor ) with an organic compound of the type R-X ( R denotes an alkyl or aryl radical , X an electron-withdrawing heteroatom ). The heteroatom is replaced by the nucleophile (see substitution reaction ).
General example of nucleophilic substitution in which X stands for a halogen - such as chlorine, bromine or iodine:
|Haloalkane + nucleophile –––––> substitution product + halide
Nucleophilic substitution reactions are mostly carried out in solution . The polarity of the solvent and the influence of substituents in the starting materials are of decisive importance for the speed of the reaction. If the solvent itself is the nucleophilic reaction partner, one speaks of solvolysis .
The heteroatom or the heteroatom-containing group can be substituted by a nucleophile in the following compounds:
- Alkyl halides : alkyl chlorides and alkyl bromides
- Aryl halides : aryl chlorides and aryl bromides
- Carboxylic acid derivatives , such as chlorides , esters , and anhydrides
- Sulfonic acid esters, e.g. B. tosylates ( p -toluenesulfonic acid esters) or mesylates (methanesulfonic acid esters) or the particularly reactive triflates (trifluoromethanesulfonic acid esters )
- Oxirane - thiirane - and aziridine rings (→ heterocycles )
Nucleophilic substitutions are observed in aliphatic and aromatic compounds: there are aliphatic nucleophilic substitutions and aromatic nucleophilic substitutions , the former being much more common.
In addition, the reactions are divided into different groups based on their molecularity . This means that the reactions are classified according to how many molecules are involved in the rate-determining step of the reaction . The described mechanisms S N 1 and S N 2 are to be understood as extreme cases of nucleophilic substitution. The transition between them is fluid. A summary of both reactions can be found in the following table:
|Summary of the S N 1 and S N 2 reaction
|S N 1
|S N 2
|v = k · c [substrate]
(1st order reaction)
|v = k · c [substrate] · c [nucleophile]
(2nd order reaction)
|never, except with stabilizing groups
|excellent except for hindered nucleophile
|moderate, except for tertiary benzyl
|moderate, except for tertiary allyl
|Racemization with substitution at the stereocenter
Inversion (chemistry) with substitution at the stereocenter
by Walden reversal
|mostly, especially with basic nucleophiles
|only with heat and basic nucleophile
The S N i mechanism is a special case that will be discussed separately.
Aromatic nucleophilic substitutions usually take place in two stages , i.e. the intermediate products can often be isolated (see Meisenheimer complexes ). In addition, a so-called dehydrobenzene mechanism is known, which is also referred to as the aryne mechanism .
S N 1 mechanism
In the S N 1 reaction, “S N ” stands for a nucleophilic substitution and the “1” for a “monomolecular” mechanism that proceeds in two stages, but in which only one molecule is involved in the rate-determining step.
Kinetics of the S N 1 reaction
An attempt can be made to infer the reaction mechanism from the rate law of a reaction. The S N 1 reaction only depends on the concentration of the substrate. The reaction rate v is thus calculated using the rate law from a rate constant k and the concentration of the substrate c [substrate]:
The rate of reaction is primarily dependent on the substrate and, in the zero order, on the nucleophile (i.e. not at all). So the overall order of the reaction is one. Although the reaction mechanism consists of two steps, the reaction rate depends only on the slowest reaction step; this is the step that determines the speed. The speed-determining step can be compared to a bottle neck : The speed at which water can flow into a bottle is only controlled by the narrowest part of the bottle - the bottle neck.
The S N 1 reaction takes place in two steps. In the first, rate-determining (= slowest) step , the compound RX dissociates and releases the leaving group X - as an anion . What remains is a planar, sp 2 -hybridized carbocation (carbenium ion) R + . This reactive intermediate (R + ) is attacked by the nucleophile Nu in the second step. This second step is very quick compared to the first. In contrast to the S N 2 reaction, the nucleophile is not involved in the rate-determining step . In addition, the S N 1 mechanism is favored by a relatively small initial concentration of the starting materials. However, if several nucleophiles are available, the stronger nucleophile is predominantly found in the product.
Theoretically, the subsequent attack by the nucleophile is equally likely from both sides. A racemic product would be the result, since the attack from the side opposite the leaving group would result in a configuration change ( inversion ), which would result in the retention of the configuration ( retention ) from the same side . Experimentally, one often finds more products with a configuration change (yield 50–70%); This is due to the fact that after the leaving group has been split off, this leaving group does not diffuse through the solvent quickly enough and thus blocks this direction of attack. The leaving group cannot move away sufficiently before the nucleophilic attack and thus represents a hindrance for the attacking nucleophile . This sometimes leads to an increased inversion of the configuration . In such a case one speaks of a partial racemization.
In reactions according to S N 1, however, all stereochemical possibilities from complete inversion to racemization were observed , with the formation of a racemate being the rule.
- Polarity of the solvent: the more polar the solvent, the better it can stabilize the S N 1 reaction through hydrogen bonds and thereby accelerate the reaction. This effect is particularly evident in a protic solvent. The S N 1 reaction benefits from such solvents, since both the transition state and the intermediate are polar or charged. The transition state of the rate-determining step of the S N 1 reaction is initially polar due to charge separation: the negatively charged leaving group is removed, leaving a positively charged carbocation behind. The resulting intermediate is a charged compound (the carbocation), and a negatively charged nucleophile is released. In the S N 2 reaction, on the other hand, the transition state is not polar, since charge is only shifted, but not generated.
So it can be said that the S N 1 reaction is preferred by protic solvents .
- Quality of the leaving group: Since the leaving group leaves the molecule in the rate-determining step, the rate of the reaction is strongly influenced by its quality. The leaving group is often negatively charged. The ease with which it leaves the molecule is related to its ability to stabilize this negative charge. This ability to stabilize charge is all the stronger the less basic the nucleophile X - is or the more acidic the conjugate acid HX is. ( Nucleofugy )
- Substrate structure: The higher a carbon atom is substituted, the faster the S N 1 reaction takes place on it. A tertiary alkyl reacts faster than a secondary alkyl and this reacts faster than a primary alkyl, this is due to the stability of the carbocations. This stability is related to hyperconjugation and the + I effect: alkyl groups supply the carbocation as substituents with electron density and in this way reduce the positive charge. In this way, on the one hand, the carbocation is stabilized and also dissociates more easily. Primary alkyls are so unstable that they no longer enter into an S N 1 reaction.
Another factor is that as the substitution increases, steric strain is reduced.
Allyl residues also have a mesomeric stabilizing effect and thus stabilize the carbenium ion as well as benzyl substituents.
- Carbocation rearrangement: A carbocation can rearrange itself through a hydride or methyl shift if a more stable compound is formed. A tertiary carbocation, for example, can arise from a secondary one. Different products can arise if the S N 1 and S N 2 reactions take place on the same molecule.
S N 2 mechanism
S N 2 stands for a nucleophilic substitution with a bimolecular mechanism that takes place in one step and in which both molecules are involved in the rate-determining step.
Kinetics of S N 2 reactions
The rate law provides insight into the reaction mechanism . In kinetic studies, the reaction rate v is dependent on the concentration of the substrate c [substrate] and the concentration of the nucleophile c [nucleophile], which together with a rate constant k leads to the following rate law:
The rate law is explained by the reaction mechanism, which only consists of a single step - this is of course also the rate-determining step. In this case, the leaving group emerges with the attack of the nucleophile. The reaction speed increases proportionally with an increasing number of attacking molecules (increasing concentration of the nucleophile) as with an increasing number of attacked molecules (increasing substrate concentration), since both increase the probability of a successful collision . Since two molecules are involved in the rate-limiting step of the S N 2 reaction, it is a second order reaction . In the S N 2 reaction, the “S” stands for substitution, the “N” for nucleophilic and the “2” for bimolecularity or the 2nd order. Since bond formation and breaking take place simultaneously in the S N 2 reaction, it is a concerted reaction . At the same time, this means that the reaction takes place without any detectable intermediate products and has only one transition state.
The S N 2 reaction always proceeds via a backside attack; this means that the nucleophile attacks from the opposite side to which the leaving group is attached. This can be explained by the fact that the attacking nucleophile would stand in the way of the negatively charged leaving group if both were on the same side. For a more powerful explanation, however, the molecular orbital theory is necessary:
In order to form a chemical bond, the HOMO of one molecule has to interact with the LUMO of the other molecule. In the S N 2 reaction, the occupied non-bonding molecular orbital (HOMO) of the nucleophile must interact with the unoccupied, antibonding molecular orbital (LUMO) of the carbon compound. In the case of a rear-side attack, there is a binding interaction, but in a front-side attack, binding and antibonding interaction occurs at the same time. Therefore, the successful attack of a nucleophile always occurs from the back. The necessity of attack on the back also explains that with increasing methylation of an alkane (the replacement of hydrogen atoms by methyl groups), the rate of reaction continuously decreases.
Before the reaction, the carbon atom is sp 3 -hybridized, i.e. tetrahedral. During the reaction, the nucleophile approaches the positively polarized carbon nucleus; in the transition state, a trigonal bipyramid with weakly bound axial ligands forms. This means that the binding electron pairs of the three residues, which are not involved in the actual reaction, move into the same plane and the nucleophile and the leaving group on their respective side face each other like the tips of a pyramid on an axis perpendicular to the plane described. The whole reaction is to be understood as a smooth transition. The bonds between carbon and nucleophile as well as carbon and leaving group are each weakened because it is a 3-center-4-electron bond .
This mechanism results in an inversion of the configuration of the carbon atom; this is called the Walden inversion or "Krieger's umbrella principle" because the tetrahedral arrangement of the carbon is reminiscent of an umbrella that is turned upside down during the reaction as if by a gust of wind. This inversion only plays a role in chiral molecules. As a result of this inversion, an ( S ) -connection named after the Cahn-Ingold-Prelog nomenclature would become an ( R ) -connection. The inversion can be used to specifically synthesize a certain enantiomer. If the configuration is to be retained, two successive S N 2 reactions can be carried out; this leads to a retention of the configuration.
- The course of the S N 2 reaction is shown. On the left-hand side, the carbon atom is tetrahedral , as is the right-hand side , and trigonal-bipyramidal in the middle with five bonds; the radicals R 1 to R 3 are all axially in one plane.
In addition, the course of the reaction is favored by a relatively high initial concentration of both starting materials. On the other hand, water suppresses the S N 2 reaction.
The Walden reversal leads to inversion at the stereochemical center.
- Solvent polarity: the better a nucleophile is solvated, the worse it is. The choice of solvent should be made accordingly. The S N 2 mechanism takes place preferentially in polar aprotic solvents.
- Leaving group / nucleofugation: see S N 1
- Nucleophilicity: The goodness of a nucleophile is called nucleophilicity. The nucleophilicity depends on the charge, the basicity and the polarizability of the nucleophile, the solvent and the substituents. Additional negative charge increases the nucleophilicity. This means that a base is always more nucleophilic than its conjugate acid. This is due to the fact that the bond to the electrophilic carbon atom, which is formed when the nucleophile is attacked, can form all the more easily the more electronically rich the nucleophile is. The stronger base is also the stronger nucleophile. As a result, the nucleophilicity in the periodic table decreases from left to right. However, this trend is of less importance than the presence of a charge.
- Substrate structure: the higher a carbon atom is substituted, the slower the S N 2 reaction takes place on it. The reaction rate v of: S N 2 reactions at a tertiary carbon atom do not actually take place, but are displaced by competition from side reactions (like the S N 1 reaction). The decrease in the reaction rate results from the space required by the methyl groups. Since a methyl group takes up a larger volume than a hydrogen atom, it blocks the possible attack of the nucleophile - this is called steric hindrance . The steric hindrance increases not only with the number but also with the length of the alkane residues - the longer they are, the more they hinder a possible reaction or the more they reduce the reactivity of the molecule in an S N 2 reaction. Branches at the Cα-carbon increase the steric demand and thus prevent the reaction even more.
Competition between S N 1 and S N 2 reactions
The S N 1 and S N 2 reactions are in competition with one another. In the synthesis of a compound, one would prefer an S N 2 reaction to an S N 1 reaction because the S N 2 reaction leads to a single product, but the S N 1 reaction leads to a mixture of at least two products Carbocation rearrangement is further complicated. Thus, an attempt is made in a synthesis to create the conditions for an S N 2 reaction. The following factors influence whether a reaction proceeds according to an S N 1 or S N 2 mechanism:
- the structure of the connection
- the concentration of the nucleophile
- the reactivity of the nucleophile
- the solvent
When it comes to the structure of the compound, it is initially decisive whether the carbon atom that bears the group to be substituted is a primary, secondary or tertiary carbon atom. The first, dependent effect, is that, with increasing degree of alkylation, the carbocation resulting from an S N 1 reaction can be stabilized better and better by I-effects and hyperconjugation . So z. B. an S N 1 reaction on tert -butyl bromide more easily than on 2-bromopropane .
The second effect, as already mentioned, results from steric hindrance . Since the S N 2 reaction takes place via a rear-side attack and this is made more difficult by the space required by the alkyl groups, an S N 2 reaction becomes more difficult with increasing alkylation. So z. B. an S N 2 reaction on 2-bromopropane easier than on tert -butyl bromide . Thus, with increasing alkylation, an S N 2 reaction becomes more difficult, while an S N 1 reaction is made easier.
The dependence of the S N 1 and S N 2 reactions on the concentration and reactivity of the nucleophile can be understood by considering the rate law. The rate law for an S N 2 reaction reads :
An S N 2 reaction is therefore dependent on the concentration of the starting material and the concentration of the nucleophile. The rate law for an S N 1 reaction is:
The reaction speed is therefore only dependent on the concentration of the reacting molecule. If, as in the case of a competitive situation, both reactions can take place, then the rate law of the overall reaction reads:
From the rate laws it can be seen that the concentration of the nucleophile has an influence on S N 2 reactions, but not on S N 1 reactions. It thus follows that in a competitive situation between S N 1 and S N 2 reactions, the S N 2 reaction can be promoted by increasing the concentration of the nucleophile.
Another possibility for preferring the S N 2 reaction is to change the quality (reactivity) of the nucleophile. An S N 2 reaction only consists of a single step: the nucleophile displaces the leaving group. An S N 1 reaction, on the other hand, consists of the first, slow step (which is therefore rate-determining), in which the leaving group detaches from the molecule, and a second, rapid step, in which the nucleophile reacts quickly with the resulting molecule. A good nucleophile will thus accelerate an S N 2 reaction, but not an S N 1 reaction.
The stability of the resulting cation is influenced by its solvent. Cations and anions can be stabilized in polar solvents by solvation . For example, the nucleophilicity can be reduced by hydrogen bonds, so nucleophiles are more reactive in aprotic solvents and S N 2 reactions proceed faster, whereas S N 1 reactions take place more in protic solvents.
S N 2 mechanisms on the unsaturated carbon atom
If one considers chlorine-substituted unsaturated compounds such as vinyl chloride (C 2 H 3 Cl) or chlorobenzene (C 6 H 5 Cl), it is found that these unsaturated compounds are only very poorly attacked by nucleophiles such as the hydroxide ion or the amide ion . Alkyl halides, i.e. the saturated halogen compounds, usually react at room temperature, while the reaction of chlorobenzene with hydroxide ions requires temperatures of 200 ° C. The increased electron density on the unsaturated carbon atoms is responsible for this inert behavior . This makes attack by a nucleophile more difficult; Unsaturated carbon atoms attract the shared pair of electrons of the group to be substituted (e.g. the C-Cl bond in vinyl chloride or in chlorobenzene) more strongly, which makes it difficult to abstract the chlorine atom.
The introduction of electron-withdrawing groups in benzene and its substituted derivatives led to the discovery of a new pathway known as S N 2 (aromatic) . If one considers chlorobenzene and compares the reaction rate in the case of a nucleophilic attack with the reaction of p-nitrochlorobenzene, one finds a considerable increase in the conversion rate. The exact mechanism is described in the article Nucleophilic Aromatic Substitution .
S N 2t mechanism
An S N 2t reaction is understood to be the attack of a nucleophile on an sp 2 -hybridized carbon atom, which is particularly strongly positively polarized. This reaction is often referred to as an addition-elimination reaction on the carboxylic acid or its derivatives. A rehybridization of sp 2 to sp 3 takes place, which is why a tetrahedral intermediate is formed (the t in S N 2t stands for tetrahedral). The best leaving group then emerges and the carbon atom rehybridizes to sp 2 . An example of this is the acid-catalyzed esterification of carboxylic acids with alcohols. The carboxy group is first protonated and the nucleophile, in this case an alcohol, can attack. After further protonation, water can emerge as a good leaving group.
S N i mechanism
The production of alkyl chlorides by nucleophilic substitution of alkanols with thionyl chloride takes place according to a so-called S N i mechanism. An alkyl chloride with the same configuration is obtained from an enantiomerically pure alkanol as starting material. The S N i reaction thus proceeds with retention (retention of the configuration). Whether an S N i reaction or an S N 2 reaction takes place depends on the solvent. The attacking nucleophile, in this case a chloride ion, must not be dissolved in the solvent, so diethyl ether is used in the S N i reaction . As a result, the chloride ion can only be transferred internally. If, on the other hand, pyridine is used as the solvent, an S N 2 reaction takes place.
Neighbor group participation
Nucleophilic substitutions can also be controlled by internal molecular processes. Thus, the substituents already bonded to the hydrocarbon under consideration may participate. This intramolecular reaction is preferred because there is a high probability of colliding with the substituents on the neighboring carbon atom. This nucleophile can e.g. B. not be removed from the substrate by the solvent.
Here the neighboring group (substituent) acts as a nucleophile, which can cleave the leaving group by attacking it on the back. A cyclical system is formed temporarily. Such a cycle can be opened on the one hand by high ring tension (small rings) or on the other hand by an attack by an external nucleophile. In the second case, the retention product is obtained with double inversion.
Substitution on the alkyl carbon or aryl carbon
Oxygen as a nucleophile
- Alkyl chlorides react with hydroxide ions to form alcohols , releasing chloride ions. In the same way, chlorinated aromatics react to form phenols :
- Aliphatic ethers and phenol ethers can be obtained by nucleophilic substitution of chloride by alcoholates on alkyl or aryl chlorides. This reaction is also known as the Williamson ether synthesis .
Nitrogen as a nucleophile
- Aliphatic primary amines are formed by replacing the halide with the amino group (-NH 2 ). This reaction takes place in ammonia as a solvent and is also known as ammonolysis .
- To obtain secondary amines, the reaction is not carried out in ammonia but with another amine as solvent (→ aminolysis ).
- Tertiary amines result from the reaction with a secondary amine,
- Tetraalkylammonium salts by reaction with a tertiary amine.
- The Gabriel synthesis includes a reaction in which an alkyl chloride or bromide is reacted with the phthalimide anion :
Sulfur as a nucleophile
- The reactions of alkyl and aryl halides with hydrogen sulfide and thiolates lead to thiols and thioethers analogously to those with the oxygen homologues hydroxide and alcoholates .
Halides as a nucleophile
- If alkyl or aryl chlorides or bromides are reacted with an excess of fluoride (in polar, aprotic solvents) or iodide (in acetone), aliphatic or aromatic fluorides or iodides are formed. The reaction with iodide is called the Finkelstein reaction .
Phosphorus as a nucleophile
- Alkyl chlorides react with alkyl or aryl phosphanes to form the corresponding phosphonium salt . The olefination reagents for the Wittig reaction are obtained from organic phosphonium salts .
Hydride as a nucleophile
- Alkanes can be prepared by reacting alkyl halides with hydride as a substituent . The hydride donor is lithium aluminum hydride .
The elimination reaction as a possible competitive reaction
E1 competes with the S N 1 reaction, E2 with the S N 2 reaction. This can be controlled, among other things, by the influence of solvents.
see also: Elimination reaction
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