Nucleophilic substitution

The nucleophilic substitution reaction is a type of organic chemistry. Here, a nucleophile reacts in the form of a Lewis base ( electron pair ) with an organic compound of the type R -X ( R is an alkyl or aryl radical, X is an electron-withdrawing heteroatom). The heteroatom is replaced by the nucleophile (see substitution reaction).

General Example for the nucleophilic substitution, in which X is a halogen - such as chlorine, bromine or iodine - is:

In inorganic chemistry, this type is also to be found, an example is the hydrolysis of silicon tetrachloride.

• 3.1 SN1 mechanism 3.1.1 Kinetics of SN1 reaction
• 3.1.2 mechanism
• 3.1.3 Stereochemistry
• 3.1.4 Factors

• 3.2.1 Kinetics of SN2 reactions
• 3.2.2 mechanism
• 3.2.3 Factors

• 4.1 substitution on the alkyl carbon and aryl carbon 4.1.1 oxygen as a nucleophile
• 4.1.2 nitrogen nucleophile
• 4.1.3 sulfur nucleophile
• 4.1.4 halides as a nucleophile
• 4.1.5 phosphorus as a nucleophile
• 4.1.6 Hydride as a nucleophile

General characteristics

Nucleophilic substitution reactions are usually carried out in solution. Here, the polarity of the solvent and the Substituents in the starting materials is crucial for the velocity of the reaction. If the solvent is itself the nucleophilic reactant, one speaks of a solvolysis.

Reactants

Nucleophiles

As nucleophiles various compounds can be used. This is an anion or electron-rich molecules with lone pairs (see examples below).

Type R- X

The attacked molecule RX has a strong polar bond ( unequal distribution of the electron density ), for example, C -Cl, C -Br, CO, C = O or Si -Cl.

In the following compounds the heteroatom or heteroatom - containing group can be substituted by a nucleophile:

• Alkyl halides: alkyl chlorides and bromides
• Aryl halides: aryl chlorides and bromides
• Carboxylic acid derivatives such as chlorides, esters, and anhydrides
• Sulfonic acid esters, such as tosylates (p- toluenesulfonate ) or mesylate ( methanesulfonate ) or the particularly reactive triflate ( trifluoromethanesulfonate ester )
• Oxirane, thiirane and aziridine rings ( → heterocycles )

Mechanisms

Nucleophilic substitutions are observed in aliphatic and aromatic compounds: aliphatic nucleophilic substitutions and there are aromatic nucleophilic substitutions, the former being much more widespread.

In addition, the responses due to the molecularity be divided into different groups. That is, the reactions are then arranged, the number of molecules in the rate- determining step of the reaction involved. The described mechanisms SN1 and SN2 are to be regarded as extreme cases of nucleophilic substitution. The transition between them is smooth. A summary of both reactions can be found in the following table:

The SNI mechanism is a special case which will be discussed separately.

Aromatic nucleophilic substitutions usually run from two stages, that is, the intermediates are often isolable (see Meisenheimer complexes). In addition, a so-called benzyne mechanism is known, which is also referred to as Arinmechanismus.

SN1 mechanism

Wherein SN1 reaction "SN" is a nucleophilic substitution and "1" for a monomolecular mechanism although two stages passes, but in which only one molecule is involved in the rate determining step.

Kinetics of SN1 reaction

From the rate law of a reaction may be trying to close on the reaction mechanism. Wherein SN1 reaction is found exclusively a function of the concentration of the substrate. The reaction rate v is therefore calculated using the rate law of a rate constant k, and the concentration of the substrate c [ substrate ]:

The reaction rate depends to first order from the substrate and zero order of the nucleophile (ie not at all). The overall order of the reaction is therefore one. Although the reaction mechanism consists of two steps, but the reaction speed is dependent on the slowest reaction step; this is the rate-determining step. The rate determining step may be compared with a neck: The rate at which water can flow into a bottle, is controlled only by the narrowest point of the bottle - the bottle neck.

Mechanism

The SN1 reaction proceeds in two steps. In the first, rate-limiting ( = slowest ) step dissociates the compound RX and sets the leaving group X as a free anion. What remains is a planar sp2 -hybridized carbocation ( carbenium ion ) R . This reactive intermediate ( R ) is attacked in the second step of the nucleophile Nu. This second step is very fast relative to the first. The nucleophile is not involved in the rate -limiting step in contrast to the SN2 reaction. Ideal for SN1 reactions are compounds which form relatively stable carbocations ( resonance-stabilized, or tertiary carbon atoms) and a polar protic solvent. In addition, the SN1 mechanism is favored by a relatively small initial concentration of the reactants. But there are several nucleophiles available so you can find in the product mainly the stronger nucleophile again.

Stereochemistry

The rate-determining step in the SN1 mechanism is the formation of ideally planar carbocation. The configuration of the starting compound is thereby canceled.

Theoretically, the subsequent attack of the nucleophile from both sides is equally likely. A racemic product would be the result, since the attack from the opposite side of the leaving group a configuration change ( = inversion), which would have the same side of the retention of configuration (retention ) result. Experimentally, one often finds more products with a configuration change ( yield 50-70%); This is because that after cleavage of the leaving group this leaving group is not fast enough to diffuse through the solvent and thus blocks this attack direction. The leaving group can before the nucleophilic attack does not remove sufficient and thus provides for the attacking nucleophile disability dar. This sometimes leads to an increased inversion of configuration. In such a case one speaks of a partial racemization.

Were observed in SN1 reactions, however, all stereochemical possibilities of complete inversion to racemization, the formation of a racemate is the rule.

Factors

• Polarity of the solvent: the more polar the solvent, the better it may be the SN1 reaction stabilized by hydrogen bonds, thereby accelerating the reaction. The clearest reflection of this effect is evident in a protic solvent. The SN1 reaction benefits from such solvents, since both the transition state as well as intermediate are polar or charged. The transition state of the rate-determining step of the SN1 reaction is polar first by charge separation: The negatively charged leaving group moves away and leaves a positively charged carbocation back. The resulting intermediate product is a charged compound ( the carbocation ), also a negatively charged nucleophile is released. In the SN2 reaction on the other hand, the transition state is non-polar, since charging is only shifted but not generated. It can therefore be said that the SN1 reaction of protic solvents is preferred, the SN2 reaction, however, aprotic solvents.

• Quality of the leaving group: Since the rate-determining step, the leaving group leaves the molecule, the reaction rate is strongly influenced by their quality.

• Substrate structure, the higher a carbon atom is substituted, the faster the reaction proceeds SN1 him. Thus, a tertiary alkyl responds faster than a secondary alkyl and this faster than a primary alkyl, this is due to the stability of the carbocation. This stability is due to hyperconjugation and together I effect: alkyl groups provide the carbocation as substituents electron density and thus reduce the positive charge. On the one hand the carbocation is stabilized and also dissociates more easily. Primary alkyls are so unstable that they do not undergo SN1 reaction more. Another factor is that, with increasing substitution steric strain is reduced.

Also allyl act mesomeriestabilisierend and thus stabilize the carbenium ion, as well as benzyl.

• Carbocation rearrangement: A carbocation can rearrange by a hydride or methyl shift, so if a more stable compound. From a secondary can arise, for example, a tertiary carbocation. This helps to create different products if SN1 and SN2 reaction run on the same molecule.

SN2 mechanism

SN2 is a bimolecular nucleophilic substitution with a mechanism which proceeds in one step and in which both molecules are involved in the rate determining step.

Kinetics of SN2 reactions

Insights into the reaction mechanism provides the rate law. Kinetic studies can be found in a dependence of the reaction rate on the concentration of the substrate v c [ substrate ] and the concentration of the nucleophile c [ nucleophile ], which, together with a rate constant k of the following velocity law:

The rate law is explained by the reaction mechanism, which consists of only a single step - this is of course also the rate-determining step. This occurs over time with the attack of the nucleophile, the leaving group. The reaction rate also increases proportionally with an increasing number of target attacking molecules ( increasing concentration of the nucleophile ), as with increasing number of compromised molecules ( increasing substrate concentration ) as these increase the likelihood of a successful collision. Since the SN2 reaction the rate-determining step, two molecules are involved, it is a second-order reaction. In the SN2 reaction is the "S" for substitution, the "N" for nucleophilic and the " 2" for the Bimolekularität or 2nd order. The term " nucleophile " comes from the lone pair of the attacking particle. Means nucleophilic " core -loving ," meaning that the nucleophile is attracted by the positively charged core. Since the SN2 reaction bond formation take place and break at the same time, there is a concerted reaction. This also means that the reaction proceeds without detectable intermediates, and has only a transient state.

Mechanism

The SN2 reaction goes via a backside attack; This means that the nucleophile attack from the opposite side, where the leaving group is bound. This can be explained by the fact that the attacking nucleophile of negatively charged leaving group would be in the way, if both were on the same page. For a more powerful explanation, however, the molecular orbital theory is necessary:

To form a chemical bond, the HOMO of a molecule must contact with the LUMO of the other molecule to interact. In the SN2 reaction, the occupied nonbonding molecular orbital must be received by an interaction of the carbon compound (HOMO ) of the nucleophile with the unoccupied antibonding molecular orbital ( LUMO). In a back-side attack it comes to binding interaction, with a front -side attack, however, to be bound and antibonding interaction simultaneously. Therefore, the successful attack of a nucleophile is always from the back side.

The need for a back attack out also stated that with increasing methylation of an alkane ( the replacement of hydrogen atoms by methyl groups ) decreases the reaction rate continuously. The reaction speed v of:

SN2 reactions on a tertiary carbon atom in fact not run from, but are displaced by competing side reactions (such as the SN1 reaction). The decrease in the reaction rate caused by the steric bulk of the methyl groups. Since a methyl group occupies a larger volume than a hydrogen atom, it blocks the potential of attack of the nucleophile - this is called steric hindrance. The steric hindrance increases not only the number but also with the length of alkane radicals - the longer they are, the more strength they hinder a possible reaction or the more they reduce the reactivity of the molecule in an SN2 reaction.

Before the reaction, the carbon atom of sp3 hybridized exists therefore tetrahedral. During the reaction, the nucleophile approaches the positively polarized carbon core; in the transition state to form a trigonal bipyramid with weakly bound axial ligands. This means that the bonding electron pairs of the three residues that are not involved in the actual reaction, back into the same plane and the nucleophile and the leaving group on their side as the peak of a pyramid face perpendicular to the described level on one axis. The whole reaction can be understood as a smooth transition. The bonds between carbon and a nucleophile and carbon and the leaving group, respectively weakened because it is a 3-center -4- electron bond.

For this mechanism results in an inversion of the configuration of the carbon atom; this is called Walden inversion or " umbrella principle according warriors " because the tetrahedral arrangement of the carbon is reminiscent of an umbrella is inverted during the reaction as indicated by a gust of wind. This inversion plays a role only in chiral molecules. By this inversion would thus from one by Cahn-Ingold- Prelog nomenclature named (S) - a compound (R)- compound. The inversion may be used to synthesize a particular enantiomer specifically. If the configuration remain intact, two consecutive SN2 reactions can be carried out; This leads to a retention ( preservation ) of the configuration.

SN2 mechanism is preferably carried out in polar aprotic solvents, and on primary carbon atoms, as there is a steric hindrance at tertiary carbon atoms. In addition, the course of the reaction is favored by a relatively large initial concentration of both reactants. However, water suppresses the SN2 reaction.

Factors

• Leaving Group: The leaving group is often negatively charged. The ease with which it leaves the molecule, is connected with their ability to stabilize these negative charge. This ability to stabilize charge, is the stronger, the less basic the nucleophile X is or the more acidic the conjugate acid HX is. When halogens is the outlet of assets:

• Nucleophilicity: The quality of a nucleophile is called nucleophilicity. Nucleophilicity depends on the charge, the basicity and polarizability of the nucleophile, the solvent, and the substituents.

Competition between SN1 and SN2 reaction

The SN1 and SN2 reaction compete with each other. In the synthesis of a compound would be an SN2 reaction before SN1 reaction preferable because the SN2 reaction to one product, but results in the SN1 reaction to a mixture of at least two products, and is further complicated by carbocation rearrangement. Thus, attempts at synthesis to produce the conditions for a SN2-type reaction. Whether a reaction more likely proceeds by an SN1 or SN2 mechanism is influenced by the following factors:

• The structure of the compound
• The concentration of the nucleophile
• The reactivity of the nucleophile
• The solvent

In the structure of the compound is first depends on whether the carbon atom which carries the substituent group to a primary, secondary or tertiary carbon atom. The first, which is dependent effect is that with increasing degree of alkylation, the resulting in an SN1 reaction carbocation can be increasingly better stabilized by I- effects and hyperconjugation. So, for example, runs an SN1 reaction of tert -butyl bromide easily than of 2- bromopropane. The second effect is, as mentioned above, by steric hindrance. Since the SN2 reaction to proceed over a backside attack and this is complicated by the space requirements of alkyl groups, a SN2 reaction with increasing alkylation becomes more difficult. So a SN2 reaction of 2- bromopropane runs eg from tert -butyl bromide easier than to. Thus, an SN2 reaction a SN1 reaction is more difficult with increasing alkylation, however, relieved.

The dependence of the SN1 and SN2 reaction of concentration and reactivity of the nucleophile can be understood by a consideration of the velocity Act. That is the rate law for an SN2 reaction:

An SN2 reaction is therefore dependent on the concentration of the starting material and the concentration of the nucleophile. The rate law for an SN1 reaction is:

The reaction rate is therefore dependent only on the concentration of the reacting molecule. If, as in the case of a competitive situation, can run both reactions, that is the rate law for the overall reaction:

The speed law is to be appreciated that the concentration of the nucleophile has an influence on SN2 reactions, but not to SN1 reactions. Thus it follows that in a competitive situation between SN1 and SN2 reaction, the SN2 reaction can be promoted by increasing the concentration of the nucleophile. Another way to favor the SN2 reaction is the change in the quality ( reactivity) of the nucleophile. An SN2 reaction consists of only a single step: the nucleophile displaces the leaving group. In contrast, an SN1 reaction consists of the first, slow step ( the order is rate-limiting ), in which the leaving group from the molecule dissolves and a second, fast step in which the nucleophile reacts rapidly with the resulting molecule. A good nucleophile is thus accelerate an SN2 reaction, a contrast SN1 reaction does not.

SN2 mechanisms at the unsaturated carbon atom

Considering chlorine-substituted unsaturated compounds such as vinyl chloride ( C2H3Cl ) or chlorobenzene ( C6H5Cl ), it is found that these unsaturated compounds are only very poorly attacked by nucleophiles such as hydroxide ion or the amide ion. Alkyl halides, that is, the saturated halogenated compounds, usually already react at room temperature, while in the reaction of chlorobenzene with hydroxide ions temperatures of 200 ° C are necessary. Responsible for this inert behavior of the increased electron density on the unsaturated carbon atoms. Thus, the attack of a nucleophile is difficult; unsaturated carbon atoms attract the shared pair of electrons to the substituent group (eg, the C- Cl bond in vinyl chloride or chlorobenzene) to be stronger, which makes the abstraction of the chlorine atom.

The introduction of electron-withdrawing groups in the benzene and its substituted derivatives, led to the discovery of a new pathway, which is referred to as SN2 ( aromatic). Considering chlorobenzene and compares the reaction rate in a nucleophilic attack by the reaction of p -nitro chlorobenzene, one notes a significant increase in conversion rate. The exact mechanism will be described with the article nucleophilic aromatic substitution.

SN2t mechanism

Under a SN2t reaction is defined as the attack of a nucleophile to an sp2 -hybridized carbon atom, which is particularly strongly positively polarized. Often this reaction is referred to as addition-elimination reaction of the carboxylic acid or its derivatives. It takes place here rehybridization from sp2 to sp3, which is why a tetrahedral intermediate forms ( the t in SN2t stands for tetrahedrally ). Then comes out the best leaving group and rehybridized to sp2 carbon atom. An example of this is the acid-catalyzed esterification of carboxylic acids with alcohols. The carboxyl group is first protonated and the nucleophile, in this case alcohol may attack. After a further protonation water can escape a good leaving group.

SNi mechanism

The extraction of alkyl chlorides by nucleophilic substitution of alkanols with thionyl chloride is carried out by a so-called SNi mechanism. From an enantiomerically pure alkanol reactant an alkyl chloride is obtained with the same configuration. So the SNi reaction occurs with retention ( retention of configuration ). Whether a SNi reaction or a SN2 reaction takes place depends on the solvent. The attacking nucleophile, in this case a chloride ion can not be dissolved in the solvent, therefore, is used in the reaction, diethyl ether SNi. Due to the chloride ion can be transferred internally. Other hand, one uses pyridine as a solvent, an SN2 reaction takes place.

Neighboring group participation

Nucleophilic substitution can also be controlled by internal processes molecule. So it may be a contribution from the bound already at the considered hydrocarbon substituents. This intramolecular reaction is preferred, since the probability is high, with the substituents located at the adjacent C- atom to collide ( this nucleophile may, for example, are not removed by the solvent from the substrate ).

Here, the neighboring group ( substituent ) acts as a nucleophile, the leaving group which can be cleaved by a backside attack. There transitional forms a cyclic system. Such a cycle can be on the one hand by a high ring strain (small rings) or on the other hand opened by an attack of an external nucleophile. In the second case, therefore, the retention product is obtained under two-time inversion.

Examples

Substitution on the alkyl carbon and aryl carbon

Oxygen as a nucleophile

• Alkyl chlorides react with hydroxide ions to form alcohols, with the release of chloride ions. Similarly respond chlorinated aromatics to phenols:

• Alkyl chlorides react with water to protonated alcohols and chloride ( Hydrolysis):

• Aliphatic Ether and Phenol can be obtained by alcoholates of alkyl or aryl chlorides by nucleophilic substitution of chloride. This reaction is also known as Williamson ether synthesis.

• The synthesis of esters is carried out by the substitution of chloride by carboxylic acids:

• Aryl chlorides react with cyanate to aryl cyanates and chloride:

• Aromatic sulfonic acids react in alkaline melts to phenols and sulfite.

Nitrogen as a nucleophile

• Aliphatic primary amines are formed by the exchange of the halide by the amino group (-NH2). This reaction takes place in ammonia as solvent, and is also known as ammonolysis.

• For the production of secondary amines, the reaction is not in ammonia but with another amine as the solvent is performed ( → aminolysis ).

• Tertiary amines formed by the reaction with a secondary amine,

• Tetraalkyl ammonium salts by reaction with a tertiary amine.

• The Gabriel synthesis includes a reaction in which an alkyl chloride or bromide is reacted with the Phthalimidanion:

Sulfur nucleophile

• The reactions of alkyl and aryl halides with hydrogen sulphide and thiolates result analogous to those with the oxygen homologue hydroxide and alkoxides to thiols and thioethers.

• Alkyl halides react to isothiouronium salts with thiourea.

• By substitution of the halogen with hydrogen arise sulfonic acids.

Halides as a nucleophile

• Are alkyl or aryl chlorides or bromides is reacted with an excess of fluoride ( in polar aprotic solvents), or iodide ( in acetone), arise aliphatic or aromatic fluorides or iodides. Reaction with iodide is referred to as the Finkelstein reaction.

Phosphorus as a nucleophile

• Alkyl chlorides react with alkyl or arylphosphanes to the corresponding phosphonium salt. Organic phosphonium salts the olefination of the Wittig reaction can be obtained.

Hydride as a nucleophile

• Alkanes may be prepared by reaction of alkyl halides with hydride as a substituent. Hydride donor is lithium aluminum hydride.