One of the most common and important mechanisms of organic transformations is nucleophilic substitution at a saturated carbon atom. As a result of this process, $Z$ leaving groups in $RZ$ organic substrates containing $C_sp3-Z$ bonds are replaced by $Nu$ nucleophilic reagents: in such a way that non-shared pairs of nucleophiles in the $RNu$ reaction products become electronic pairs of $\sigma$-bonds $C-Nu$, and electron pairs of $s$-bonds $C-Z$ become lone pairs of split-off leaving groups:

Leaving groups $Z$ are often called nucleofuges ("mobile in the form of nucleophiles"). A good leaving group has high nucleofugity, a poor leaving group has low nucleofugity. The groups with high nucleofugity include the triflate (OTf) group, which leaves in the form of $Z^-=CF_3SO_3^-$ anions, as well as fluorosulfonate $FSO_3^-$, p-toluenesulfonate or tosylate (OTs-), etc. low nucleofugity groups include the acetate group, $(RCOO^-)$ carboxylate ions, and $F^-$.

Nucleophilic substitution reactions are classified according to the change in charges in the substrates or nucleophiles and according to the type of substitution mechanisms.

Classification of nucleophilic substitution reactions according to the charge criterion

According to the charging characteristic, such reactions are divided into four groups.

Interaction of neutral substrates with neutral nucleophiles

$Nu: + RZ \to Nu^+-R + Z^-$

For example:

Interactions of neutral substrates with anionic nucleophiles

$Nu:^- + RZ \to NuR + Z:^-$

For example:

Replacing one halogen with another

Isotopic and group exchanges

1. Cationic substrates - neutral nucleophiles

   $Nu: + RZ^+ \to Nu^+-R + Z:^-$

   For example:

   Cationic substrates - anionic nucleophiles

   $Nu:^- + RZ^+ \to NuR + Z:$

   For example:

Remark 1

It follows from the above list of reactions that, with the help of various nucleophilic substitution reactions, it is possible to synthesize practically any class of compounds of the aliphatic series.

Classification of nucleophilic substitution reactions according to the type of reaction mechanism

Depending on the types of mechanisms of nucleophilic substitution reactions, they can be divided into bimolecular ones, which are denoted as $S_N2$. As well as monomolecular, which are designated as $S_N1$.

In addition, organic reactions can be divided into three categories:

1. isomerization and rearrangement,
2. dissociation and recombination,
3. substitutions.

In this classification, reactions proceeding by the SN2 mechanism belong to the third category, and reactions proceeding by the SNl mechanism belong to the second:

Significance of nucleophilic substitution

The study of the mechanisms of nucleophilic substitution plays an exceptional role in the development of ideas about the reactions of organic chemistry, and at the same time they represent the most detailed types of transformations studied. Research into the mechanisms of nucleophilic aliphatic substitution began in the mid-1930s by two prominent scientists, K. K. Ingold and E. D. Hughes. They own brilliant fundamental works that make up the golden fund of organic chemistry. Subsequently, the studies of Ingold and Hughes were significantly modified and their theories underwent a number of changes. But the proposal by these scientists to classify substitution mechanisms into $S_N2-$ and $S_N1-$ types is still relevant and fair.

Introduction

Nucleophilic reactions

A nucleophilic reaction is a reaction in which a molecule of an organic substance is exposed to the action of a nucleophilic reagent.

Nucleophilic ("loving the nucleus") reagents, or nucleophiles, are particles (anions or molecules) that have a lone pair of electrons in the outer electronic level.

Examples of nucleophilic particles:

OH, Cl, Br, CN, H3O, CH3OH, NH3.

The structure of some nucleophilic reagents

Due to the mobility of π-electrons, molecules containing π-bonds also have nucleophilic properties:

CH3=CH3, CH3=CH–CH=CH3, C6H6 it. P.

(By the way, this explains why ethylene CH3=CH3 and benzene C6H6, having non-polar carbon-carbon bonds, enter into ionic reactions with electrophilic reagents).

1. Examples of nucleophilic reactions

Nucleophilic substitution:

The mechanism of nucleophilic substitution is indicated by the symbol SN (according to the first letters of English terms: S - substitution [substitution], N - nucleophile [nucleophile]).

Nucleophilic addition:

The designation of the mechanism is AdN (Ad - addition [attachment]).

2. Monomolecular nucleophilic substitution and elimination

Nucleophilic substitution at a saturated carbon atom is the type of organic reaction whose mechanisms have been studied in the most detail. The possibility of wide, varying the structure of reagents, the simultaneous study of kinetic and stereochemical patterns, the convenience of experimental measurement of rate constants in various solvents - all this made nucleophilic substitution reactions a convenient model process for establishing general patterns that relate the structure of organic compounds to their reactivity . It is no coincidence that it was during the study of these reactions that many general concepts were formulated that became the basis of theoretical organic chemistry. It should be borne in mind that the concepts that will be formulated and analyzed in the next two chapters have a general meaning and can be used to describe the reactivity of organic compounds and in other types of organic processes. Patterns characterizing; nucleophilic substitution reactions can be largely transferred to other nucleophilic processes: elimination reactions, substitutions in the aromatic series, additions to multiple bonds, and many others.

Our focus will be on two main issues. First, we will try to understand how the reaction mechanism depends on the structure of the reacting compounds and the conditions for its implementation. Secondly, we must learn to predict how the reactivity changes with a change in the structure of the reagents and the reaction conditions! As we will see, these dependences can be completely different for reactions proceeding by different mechanisms. This can lead not only to a qualitatively different effect of changes in structural factors on the rate of the process, but also to a complete change in its direction. Next, we will show how the patterns discussed in this and the next chapter can be used to describe other processes.

3. GENERAL CONCEPTS ON THE MECHANISMS OF NUCLEOPHILIC SUBSTITUTION REACTIONS

In general, the reaction of nucleophilic substitution can be represented by the following scheme: R -Xm + Yn → R -Yn +1+ Xm -1

Both an anion and a neutral molecule with at least one lone pair of electrons (i.e., a Lewis base) can act as a nucleophilic agent Y, for example:

Y = H3O, ROH, H3S, RSH, NH3, NR., OH", OR", SH~, SIT, Hal", CN~, SCN-, NO2, RCOCT. RC=-CHR etc.

The substitutable group X (called the leaving group) usually has a high electronegativity and can leave both as an anion and as an uncharged molecule, splitting off with the electrons of the broken bond:

X=Ha1, OH, OR,

OSO2R, OCOR, NR3, SR2, etc.

It should be borne in mind that in most cases, nucleophilic substitution reactions are accompanied by competing nucleophilic elimination reactions, since the nucleophilic reagent can interact not only with a positively charged carbon atom, but also with a hydrogen atom located in the position, splitting it off in the form proton. In this regard, many aspects of substitution and elimination reactions will be considered in parallel.

Nucleophilic substitution reactions are denoted as Sn, and eliminations as En.

As we shall see, the substitution reaction at C can proceed as a dissociative or as a synchronous process. In the first case, the reaction begins with monomolecular dissociation at the C-X bond with the formation of a carbocation, which interacts with a nucleophilic reagent in the second stage.

In the second case, the formation of a bond with a nucleophilic reagent and the breaking of a bond with the leaving group are carried out simultaneously, and the process proceeds in one stage:

RX + Y- are structures, and the substitution goes through a transition state analogous to that which takes place in the case of a synchronous process. In reactions in solution, the two-stage accocative mechanism does not occur. The fact that nucleophilic substitution reactions can actually occur via two different mechanisms is evidenced by both stereochemical and kinetic data.

4. Stereochemical course of nucleophilic substitution reactions.

When studying the reactions of nucleophilic substitution of y asymmetric carbon atom, it was shown that, depending on the structure of the initial reagents and the reaction conditions, the stereochemical course of the reaction can be different. Thus, during the next cycle of reactions, optical activity is almost completely preserved, but the sign of rotation is reversed.

In the first and third stages of the reaction, the bonds of the asymmetric carbon atom are not affected and, therefore, its configuration remains unchanged. Hence it follows that the second stage, the replacement of the p-toluenesulfonate group by the acetate anion, occurs with complete reversal of the configuration at the action center (Walden reversal).

Similar conclusions were drawn when comparing the rates of racemization and halogen exchange in optically active halogen derivatives (since the initial and final compounds are identical, radioactive halogen ions were used to study the rate of the process).

This has been shown by the labeled atom method.

If we assume that each exchange event is accompanied by configuration reversal, then when the reaction proceeds by 50%, a completely racemized product should be formed, i.e., the exchange rate should be half the rate of racemization. The experimental data are in complete agreement with this assumption. Thus, the exchange of iodine in 2-iodoctane proceeds with complete reversal of the configuration.

At the same time, many nucleophilic substitution reactions proceed with a complete loss of optical activity during each reaction. Thus, the reaction of solvolysis of optically active a-chlorobenzene in 80% aqueous acetone solution is accompanied by 97% racemization:

Kinetic nature of nucleophilic substitution reactions

Most often, nucleophilic substitution reactions are described by one of two kinetic equations.

The reaction can be described by a first order equation. In this case, the rate of the process does not depend on either the concentration or the nature of the nucleophile.

Such a kinetic equation indicates that the nucleophile does not take part in the rate-determining stage of the process and the pre-equilibrium stages preceding it. the fast stage following the rate-determining one.

In the second case, the reaction has a total second order and first order in terms of substrate and nucleophile.

These reactions are characterized by a high dependence of the rate of the process on the nature of the nucleophile.

5. S N 1 andS N 2 reactions.

The fundamental contribution to the study of substitution reactions at the sp 3-hybridized carbon atom was made by Ingold. A classic example of a nucleophilic substitution reaction is the conversion of an alkyl halide to an alcohol:

R-Cl + HO- --> R-OH + Cl-

When studying the kinetics of reactions of this type, it was found that they can proceed according to two mechanisms (monomolecular and bimolecular substitution), which correspond to kinetic dependences:

V1=k' (S N 1)

V2= k (S N 2)

The designation of reactions (S N 1) and (S N 2) was also proposed by Ingold and stands for, respectively, as nucleophilic substitution monomolecular and bimolecular (from English Substitution nucleophilic).

MONOMOLECULAR NUCLEOPHILIC SUBSTITUTION (S N 1)

BIMOLECULAR NUCLEOPHILIC SUBSTITUTION (S N 2)

It is assumed that the reaction proceeds according to the following scheme:

If any optical configuration (D -, L -) existed in the original compound, then as a result of the reaction, it is reversed (L -, D -).

Reactions of this type predominantly involve sterically unhindered primary alkyl halides, which do not form a stabilized carbocation when the leaving group is cleaved off.

6. INFLUENCE OF VARIOUS FACTORS ON NUCLEOPHILIC SUBSTITUTION AT A SATURATED CARBON ATOM

	(S N 1)	(S N 2)
The structure of the substrate	The reactivity falls in the series: benzyl, allyl > tertiary > secondary > primary	The reactivity grows in the series: benzyl, allyl< третичный < вторичный < первичный
Entering group	Virtually no effect	The greater the nucleophilicity, the more likely the reaction will proceed.
Leaving group	The lower the binding energy, the easier the reaction proceeds.	Substitution becomes more difficult as the nucleophilicity (basicity) of the leaving group increases
Steric factors	An increase in the number of alkyl substituents and electron-donating groups at the nucleophilic center promotes the reaction.	Interfere with the attack of the nucleophilic center and hinder the reaction
Solvent effect	Reactions are facilitated by protic polar solvents	The effect of the solvent is much less pronounced, but the reaction is hindered by solvents that solvate the nucleophile. In general, proceed better with aprotic polar solvents.
Nucleophile concentration	Does not affect the rate of reaction	The reaction rate is proportional to the nucleophile concentration

7. Application of nucleophilic substitution reactions

A large number of different groups can be substituted by these nucleophilic substitution reactions. Bannett and Zeiler gave the following approximate order of ease of group substitution: _ F > -N02 > -Cl, -Br, - J > -OS02R > - NRt > - OAr > -- OR > - SR, SAr > - S02 R > - NR2 .

A much less satisfactory position regarding free radical and nucleophilic substitution. In cases of free-radical substitution, the existence of n- and s-complexes has been proven; they, apparently, participate in the substitution mechanism in aromatic compounds. However, there are as yet no definite data on the existence and stability of these intermediates, and relatively little can be said about the details of the intimate mechanism of free radical substitution. In cases of nucleophilic substitution, the situation is even less satisfactory, as far as the substitution of "non-activated" aromatic compounds is concerned. At present, it is impossible to give a sufficiently substantiated explanation for substitutions of this type.

In the presence of halides or similar electronegative substituents in the ring, the whole range of nucleophilic substitution reactions becomes possible, which do not go with the original hydrocarbons themselves. These substitution reactions naturally fall into two different classes: 1) the class involving the substitution of "non-activated" ones, and 2) the class of reactions in which the "activated" substituent is substituted.

The substitution reactions of aromatic hydrocarbons are conveniently classified in terms of electronic representations of the types of substitution. Thus, for example, intermediate compounds of the R+ type with electron deficiencies tend to centers with a high electron density c. molecules with which they react. Such intermediates are called electrophilic (electron-acceptor), and substitution reactions involving such intermediates are referred to as electrophilic protection reactions http://www.anchemistry.ru/ref/8lektrofil5nogo_zame4eni9.html. Similarly, intermediates like R~: tend to the reaction centers of the molecule with low electron density and are called nucleophilic. Substitution reactions involving such intermediates are known as nucleophilic substitution reactions. Intermediate compounds in the form of free radicals, due to their electrical neutrality, are little affected by centers of high and low electron density. Substitutions involving the participation of intermediate compounds in the form of free radicals are called free radical substitution reactions.

Of the reactions of nucleophilic substitution, one can note the reactions of pyridine with sodium amide and with dry KOH at 250-300 ° C (reactions of A.E. Chichibabin):

Substitution reactions in aromatic hydrocarbons by eloctrophilic groups and free radicals were considered in the previous sections. This section is devoted to an overview of nucleophilic substitution.

The relevance of the research on the study of thiaindans, widely conducted at the Institute of Chemistry of the Academy of Sciences of the Tadya SSR, is due to the presence of the latter in the oils of the Tajik depression - the most sulphurous and resinous oil in the country. The main results of these works are contained in the report of Ph.D. I.I. Nasyrov and Corresponding Member of the Academy of Sciences of the TadkhSSR I. Nuaanov. They not only studied in detail the numerous perversions of I-thiaindanes and their derivatives, the reactions of electrophilic, radical and nucleophilic substitution, but also synthesized substances with pesticide properties, dyes, monomers, stabilizers of synthetic fibers, etc.

Norton classifies the substitution of hydrogen by metal as an electrophilic substitution reaction, based on the belief (now recognized as incorrect) that the attacking reactant is the alkali metal cation, while the carbanion plays only a minor role as a proton acceptor. On the other hand, based on the arrangement of the electron pair of the carbon-hydrogen bond that is broken and the carbon-metal (ionic) bond that is formed, the reaction of replacing hydrogen with metal can be defined as electrophilic substitution. For the same reason, the hydrolysis of tore/p-butyl chloride is defined as the reaction of nucleophilic substitution of hydrocarbon isomerization. A large number of patterns are manifested associated with the features of nucleophilic substitution reactions at the saturated carbon atom. Thus, at relatively high reaction rates, stereospecificity and stereodirectivity of rearrangements are observed, which indicates a pseudo-Sn2-substitution mechanism, which implies the preservation of the tetrahedral structure of the carbonium ion with the attack of the migrating group from the side opposite to the leaving group (hydride ion).

Conclusion

So, we examined the reactions of nucleophilic substitution in the tetrahedral carbon atom, considered two possible mechanisms of this process, showed what factors affect it, namely: the structure of the substrate, structural features of the entering and leaving groups, the nature of the solvent, various steric factors. And, finally, possible applications of reactions of this type were indicated.

Bibliography

1. T. Becker. Mechanisms of electronic processes in organic compounds.-M, 1969.-687 p.

2. Neyland O. Organic chemistry: textbook. For chem. special universities. - , M .: Higher. school., 1990.-751 p.

3. R. Morrison, R. Boyd. Organic chemistry.-M.: Mir, 1974.- 1132 p.

Nucleophilic reactions are heterolytic reactions of organic compounds with nucleophilic reagents. Nucleophiles include anions and molecules (organic and inorganic) that spend their lone pair of electrons during the reaction to form a new bond.

The rate and mechanism of the S N reaction are determined by:

Nucleophilic ability (nucleophilicity) of reagent Y

Substrate nature

Nucleofuge capacity of the leaving group

Reaction conditions

Nucleophilicity, unlike basicity, is a kinetic value, not a thermodynamic one, i.e. the quantitative measure of nucleophilicity is the reaction rate constant, not the equilibrium constant.

There are 2 limiting cases S N:

sn. Quantum chemical representations

S N can be represented as the interaction of the HOMO of the nucleophile and the LUMO of the substrate. Interaction energy:

, are the charges on the reaction center of the nucleophile Y and on the carbon atom of the substrate at which the attack occurs.

is the distance between the reacting centers.

is the coefficient of the atomic orbital of an atom belonging to a nucleophile, which is a nucleophilic center, i.e. characterizes the contribution of the nucleophile atom to the HOMO Y.

– characterizes the contribution of the carbon atom (electrophilic center) to the LUMO of the substrate.

is the change in the resonance integral, which characterizes the efficiency of overlapping of the HOMO Y and the LUMO of the substrate.

, are the energies of the HOMO Y and the LUMO of the substrate.

In the case of S N 1, when the cation and anion interact and the reaction center carries a positive charge, the Coulomb component and the relative reactivity of nucleophiles increase symbately with their basicity. In this case, the reaction is said to proceed under charge control.

The situation is more complicated in S N 2. In the gas phase and aprotic solvents, where the solvation of the anion is low and the charge on the nucleophile is more localized, charge control is also observed. However, in protic solvents (alcohols), the charge on the nucleophile is delocalized as a result of solvation. The charge on the reaction center is also small. In this case, the role of the Coulomb interaction is lower and the main contribution to the interaction energy is made by the orbital component. The reaction is said to proceed under orbital control. The presence of a donor in the nucleophile increases the charge on the reaction center, thereby increasing the contribution of the charge component, in addition, the introduction of a donor substituent leads to some increase in the HOMO energy of the nucleophile and, consequently, to an increase in the orbital component. That. the introduction of ED into the nucleophile molecule leads to an increase in the reaction rate. In the series of halogens as nucleophiles, the Coulomb interaction decreases from fluorine to iodine, which is a consequence of a decrease in the localization of the negative charge and an increase in the distance between atoms. At the same time, the orbital interaction increases because the energy of the LUMO of halogens (HOMO) increases.

Unlike S E, where the hydrogen atom is usually substituted, functional groups (halogens, sulfo-, nitro-, etc.) are replaced in S N.

The most active in nucleophilic substitution reactions should be haloalkanes RF, RCl, RBr And R.I., since in their molecules, upon substitution, stable leaving group anion X¯, which is one of the halide ions, that is, the anion of a strong acid. This is confirmed by numerous examples of substitution of halogen atoms in haloalkanes, for example, by hydroxy, alkoxy, amino, cyano, and nitro groups. On the contrary, amines should have the least reactivity, since ammonia and amines are very weak acids and, accordingly, their conjugate bases, that is, anions ¯ NH2,¯ NHR,¯ NR 2 highly reactive and therefore not stable (easily attaches a proton). The hydroxyl group in alcohols can also be replaced in reactions with many nucleophiles, however, under more severe conditions. The alkoxy group is even more difficult to replace. Hydroxyl and alkoxy groups are replaced only in an acidic medium, in which the leaving particle is not an anion, but a molecule (respectively, water or alcohol). The amino group is sufficiently resistant to substitution, cases of its nucleophilic substitution are rare, reactions proceed under very harsh conditions and only for ammonium salts. For this reason, the widest range S N-reactions of haloalkanes (ch. 3.2).

Nucleophilic substitution reactions at sp The 3-hybridized carbon atom is the most studied in organic chemistry. Just as in the case of radical substitution, here it is supposed to break the -bond in the molecule of the original substance, also called the substrate, and the formation of a new -bond in the reaction product. However, nucleophilic substitution refers to reactions of the ionic type, so the molecule of the starting material ( RX) must be polarized, and the substituent X must have a sufficiently high effective electronegativity. The general scheme of the reaction can be represented as follows:

Attack agent Y, called a nucleophile, due to the lone pair of electrons attacks the positively charged center in the substrate molecule. The reaction is accompanied by a heterolytic cleavage of the -bond in the substrate molecule, the substituent X leaves with a pair of electrons. A new covalent bond is formed by a pair of nucleophilic reagent in a coordination way.

A wide variety of particles can be nucleophilic reagents, but they must necessarily have an unshared electron pair. These are, for example, anions HO¯ , RO¯ , ¯ NH2, F¯ , Cl¯ , Br¯ , I¯ , CN¯ , H¯ , ¯ CH2-R and neutral molecules H 2 O, ROH, NH 3, RNH 2, RR'NH, H 2 S, RSH. Nucleophilic properties are also possessed by such compounds as unsaturated and aromatic hydrocarbons.

Substrates can be polar molecules having a carbon atom with an effective positive charge and a substitutable group X. The carbon atom here is called the electrophilic center. Group X also called leaving group or nucleofuge, has a high electronegativity and can leave both as an anion and as an uncharged molecule.

In nucleophilic substitution reactions, depending on the nature of the substrate, nucleophile, leaving group, and reaction conditions, several different mechanisms can be realized. For such reactions, the most common mechanism is the bimolecular nucleophilic substitution, denoted S N 2, and monomolecular nucleophilic substitution, denoted S N 1.

Mechanism of bimolecular nucleophilic substitution

The reaction is bimolecular, because it occurs when two particles collide: a nucleophile and a substrate molecule. The reaction rate in this case depends on the concentration of the substrate and on the concentration of attacking nucleophilic particles. The nucleophile attacks the positively charged center of the substrate molecule from the electrostatically more favorable "rear" side, since in this case it is not affected by the same charge of the nucleofuge. The reaction is a one-step process. Connection C–Y formed at the same time as the rupture C–X connections.

Energy required to break C–X connection, is delivered due to the synchronous process of connection formation C–Y. As soon as the group Y is included in the transition state, the group X must go, since a carbon atom cannot have more than eight electrons in its outer level. In the transition state, the original sp 3-hybridization of the carbon atom changes to sp 2 - hybridization with approximately perpendicular R- orbital. In the transition state, the nucleophilic reagent, the central carbon atom, and the nucleofuge are in a straight line; therefore, if the approach of the nucleophile from the side opposite the leaving group is impossible, for example, due to the structural features of the substrate, the bimolecular reaction also becomes impossible. The three non-reactive substrate groups and the central carbon atom are approximately coplanar, that is, they are in the same plane. They will be strictly coplanar if the incoming and outgoing groups are the same. In other cases, it is possible as an earlier transition state (the bonds of the central carbon atom have not yet adopted a trigonal configuration, the bond order S...X more communication order C...Y) and later.

The stereochemistry of the process of bimolecular nucleophilic substitution can be easily observed using the hydrolysis of an optically active substrate as an example. Three non-reacting groups, when attacked, seem to “turn inside out”. Therefore, sometimes they say about the carbon atom that it “turns out”, but most often they use the term “reversal of the configuration” of the carbon atom, meaning a change in the spatial arrangement of the groups attached to it. Indeed, if the groups X And Y had the same chemical nature (for example, in the isotope exchange reaction upon substitution 35 Cl on 37 Cl), then it would turn out that the reaction product rotates a beam of plane polarized light in the opposite direction compared to the original substance and is its mirror image. This process is compared to turning an umbrella inside out in the wind. This change in configuration is also known as "Walden inversion". All reactions of bimolecular nucleophilic substitution are accompanied by Walden inversion, regardless of the structure of the substrate.

Mechanism of monomolecular substitution

The ideal mechanism S N 1 includes two stages:

The first stage is the slow ionization of the substrate, and it is this stage that determines the rate of the reaction. The dissociation of molecules into free ions is preceded by a transition state in which the bond length increases S–X and the gradual movement of the electron pair to the leaving group. Then an ion pair is formed. Its decomposition into ions occurs almost always with the participation of polar solvent molecules. Practical mechanism S N 1 is carried out easily only in polar solvents. The second stage is the rapid interaction of the intermediate carbocation with the nucleophile.

Thus, the rate of the entire reaction as a whole depends only on the rate of the slowest first stage, in which only substrate molecules take part. Therefore, the reaction is monomolecular, and its rate depends only on the concentration of the initial substrate.

The particle formed as a result of the substitution process X¯ can slow down the reaction rate due to its reversibility. Therefore, in many cases it is possible to add salts containing anions X¯, slow down the reaction. This decrease in the reaction rate caused by the addition X¯ , called common ion effect.

In general, for S N 1-reaction rate should not depend on the nature of the nucleophile and its concentration.

The stereochemistry of monomolecular nucleophilic substitution is less unambiguous than substitution S N 2-type. Ideally, if the process involves the formation of a free carbocation, then the latter should be planar, that is, have a flat configuration corresponding to sp 2 hybridization of orbitals. The nucleophile must attack the carbocation at the same rate from both sides of the plane, which will lead to the formation of two new substrate molecules that are enantiomers with respect to each other. The result is a racemic mixture.

For many reactions, it is fairly easy to assert that, under given conditions, they follow the mechanism of either S N 1 or S N 2. However, in some cases the reaction mechanism is much more difficult to characterize. There are intermediate cases, the so-called "border" region of mechanisms, that is, the reaction mechanism is neither "pure" S N 1, nor "clean" S N 2, but belongs to the intermediate type. This can be represented by the following diagram:

where II is a tight ion pair, III is a loose ion pair, IV and V are dissociated ions, each of which is surrounded by solvent molecules.

Thus, S N 1 and S N 2-reactions can be explained by the ion-pair mechanism. The substrate dissociates with the formation of an intermediate ion pair, which then turns into products. Difference between mechanisms S N 1 and S N 2 is that in the first case, dissociated ions (IV and V) are subjected to nucleophilic attack, and in the second case, the nucleophile attacks systems I, II, and, possibly, III. Since, in the general case, a substrate can be subjected to nucleophilic attack at any stage of the transformation according to the above scheme, it can most often only be argued that one or another mechanism is close to S N 1 or S N 2.

Factors affecting the mechanism and rate of nucleophilic substitution

The same factors can affect the rate of reactions proceeding in a “pure” environment in completely different ways. S N 1or S N 2-mechanism. Therefore, some of them contribute to the flow of reactions according to a monomolecular mechanism, and some - according to a bimolecular one.

1. Influence of substrate structure. An increase in the spatial volume of substituents at the reactive center of the substrate reduces the rate of bimolecular substitution, since the reactive center becomes less accessible to attack by the nucleophile. In this case, during the transition from bromomethane to bromoethane, the rate S N 2-reaction decreases by 145 times, and to 2-bromopropane - by 18,000 times.

bromomethane bromoethane 2-bromopropane

However, the speed S N 1-reactions in this series will increase, since the influence of the electronic effects of substituents in the substrate in most cases is much stronger in monomolecular substitution reactions. Therefore, it is obvious that during the transition from primary systems to secondary and tertiary ones, the rate by this mechanism should increase. This can be explained by the increase in the stability of alkyl cations:

,

depending, in particular, on the number of methyl groups around the positively charged carbon atom, which have an electron-donating inductive effect and therefore compensate for the charge of the reaction center. In the same series, the magnitude of the superconjugation effect also increases R- orbitals of a carbocationic carbon atom with electrons S–N connections. Therefore, a high rate of nucleophilic substitution reactions can be characteristic of both primary and tertiary alkyl halides. In the first case, due to the ease of interaction on S N 2-mechanism (free access of the reaction center, no steric obstacles), in the second - according to S N 1-mechanism (ease of dissociation of substrates, stability of the resulting carbocation). Secondary alkyl halides in most cases should react according to a mixed mechanism, and their reaction rate will be relatively low, since there are obstacles to the flow of both monomolecular and bimolecular substitution.

The introduction of substituents into the substrate molecule will have a different effect on the rate of monomolecular and bimolecular reactions. Electron donor substituents should further stabilize the resulting cation and, consequently, increase the rate of monomolecular substitution.

The influence of the electronic effects of substituents on the rate of a bimolecular reaction is not so unambiguous. But most S N 2-reactions are accelerated by electron-withdrawing substituents - in these cases, the reaction rate is determined by the ease of interaction of the nucleophilic particle with the positively charged reaction center of the substrate. In other cases, the rate of a bimolecular reaction depends on the ability of the nucleofuge group to split off from the reaction center, and the influence of the nature of the substituents will be opposite - the same as in monomolecular reactions.

2. Influence of the nature of the nucleophile. In nucleophilic substitution reactions, virtually any neutral or negatively charged species with a lone pair of electrons can be a nucleophile. The rates of unimolecular reactions do not depend on the nature of the nucleophile, since it does not take part in the limiting step, therefore, the nucleophilicity of the reagent, that is, the ability to provide an electron pair for the formation of a covalent bond when interacting with a positively charged center in the substrate, affects only the rate S N 2 reactions. For these reactions occurring in solution, several basic principles can be noted that determine the effect of the nucleophile on the rate.

First, the nucleophilicity of an anion is always higher than that of the corresponding neutral molecule. So Oh stronger than H2O; ¯ NH2 stronger than NH3 etc.

Second, when comparing nucleophiles whose attacking atoms are in the same period of the periodic table, the order of nucleophilicity is approximately the same as the order of basicity. That's why

R 3 C¯> R2N¯> RO¯> F¯.

Electron donor substituents increase the nucleophilicity of the reagent, so RO¯nucleophilicity is higher than that of HO¯; at RSH- than H 2 S etc. Unstable anions, in particular carbanions, have a high nucleophilicity, since the formation of an anion for a carbon atom is energetically unfavorable (due to its low electronegativity), and therefore such particles have a high potential energy.

Thirdly, nucleophilicity increases from top to bottom in groups of the periodic system (with increasing atomic radius), although basicity decreases in this series. So, the usual order of nucleophilicity of halides is as follows: I¯ >Br¯ >Cl¯ >F¯. Similarly, any sulfur-containing nucleophile is stronger than the corresponding oxygen-containing analogue, and the same is true for compounds containing phosphorus and nitrogen. This is due to the ease of polarization of larger atoms and ions and the lower solvation energy of these ions.

Fourth, the freer the nucleophiles, the greater the rate; solvation slows down the reaction rate. Thus, protic solvents (see below) reduce the nucleophilic strength of the reagent due to the formation of hydrogen bonds if the nucleophilic center is a strongly electronegative element ( F, O, N).

However, these rules cannot take into account all the factors affecting the nucleophilicity of the reagent. Thus, steric hindrances often play a certain role. For example, tert-butylate ion (CH 3) 3 CO¯ is a stronger base than HO or C2H5O¯, but a much less strong nucleophile, since its large spatial volume makes it difficult to approach the substrate closely.

Thus, the activity of the most common nucleophiles decreases in the series (for S N 2-reactions in protic solvents):

RS¯ >C2H5S¯ >I¯ >CN¯ >HO¯ >Br¯ >C2H5O¯ >Cl¯ >CH3COO¯ >H2O.

3. Influence of solvents and catalysts. In monomolecular substitution, at the first stage, ions are formed from a neutral substrate molecule; they are easily solvated by molecules of polar solvents, especially protic ones. Therefore, protic highly polar solvents will promote the reaction according to the mechanism S N 1.

A nucleophilic particle takes part in the rate-limiting step of the bimolecular substitution. Therefore, the use of a protic solvent will lead to its deactivation due to the formation of hydrogen bonds with the hydrogen atoms of the solvent and slow down the reaction. In aprotic solvents, nucleophilic reagents retain high reactivity. In addition, by solvating cations, aprotic solvents promote the dissociation of reagent molecules into ions and, therefore, increase the nucleophilic strength of the reagent. Thus, polar aprotic solvents contribute to S N 2 reactions. Therefore, an acidic environment, as a rule, does not favor the occurrence of bimolecular reactions, and neutral or alkaline environments are preferred for these reactions, since strong nucleophiles are usually strong bases.

Lewis acids, i.e. boron, aluminum, iron, zinc, cadmium, mercury, copper and others halides, are used as catalysts in nucleophilic substitution reactions. These substances are capable of accepting anions from solution due to the valence orbitals of the metal, and their use can only slow down the process of bimolecular substitution, but promotes S N 1-process, since it facilitates the dissociation of the substrate, while the catalyst does not interact with the resulting carbocations of the substrate.

4. Influence of the nature of the leaving group. During the reaction, the leaving group is split off along with a pair of electrons.

In reactions carried out by the mechanism of monomolecular substitution, the easier it is for the leaving group to split off, the faster the reaction will go, since it is the breaking of the bond S–X and is the rate-limiting step of the reaction carried out according to the mechanism S N 1. The ease of cleavage is affected not only by the bond dissociation energy, but also by the stability of the nucleofuge group as a free particle. For example, upon detachment of halide ions, the stability of these anions decreases in the series I¯ >Br¯ >Cl¯ >F¯. However, this order is observed in an aprotic medium. On the contrary, in protic solvents or in the presence of acid catalysts, anions of weak acids are most easily eliminated, therefore splitting order will be reversed (HF the weakest acid of all halogenated acids). These reactions do not require strong nucleophiles, but do require substrates to have good leaving groups, so most monomolecular reactions proceed in an acidic environment.

For S N 2-reactions, the nature of the leaving group does not have a noticeable effect on the rate, since the limiting stage here is the formation of a transition state, and the elimination of the substituted group occurs, as a rule, quickly. But groups like Oh,OR,NH2 are difficult to remove, since the carbon-oxygen or carbon-nitrogen bond is quite strong.

Thus, the influence of various factors on the direction and rate of nucleophilic substitution reactions can be reduced to the following main provisions.

Factors contributing to leakageS N 1-reactions:

1) the formation of a stable carbocation,

2) the use of a highly polar protic solvent and acid catalysts,

3) the stability of the leaving group.

The nucleophilicity of the attacking particle is not essential.

Factors contributing to leakage S N 2 reactions:

1) the availability of the electrophilic center of the substrate,

2) the use of an aprotic solvent,

3) high nucleophilicity of the reagent.

The nature of the leaving group is not essential.

In nucleophilic substitution, the nucleophile attacks the substrate molecule, providing it with its electrons to form a new bond. The electrons of the breaking bond leave together with the released ion. Such ionic reactions proceed predominantly in the liquid phase, since the solvent stabilizes the resulting ions through solvation, which is impossible in the gas phase.

Nucleophilic substitution makes it possible to introduce into the molecule of an organic compound a large number of functional groups capable of acting as nucleophiles. For example:

Neutral molecules can also act as nucleophiles, for example:

Examples of reactions involving ethyl bromide as a substrate are given below:

A feature of nucleophilic substitution reactions is that they are one of the most common in organic chemistry, and, accordingly, one of the most studied. In particular, the study of the kinetics of the nucleophilic substitution reaction. Chemical kinetics is the study of the change in the concentration of reactants or products over time. The change is characterized by the time derivative of concentration dc/dt. Establish the relationship of the derivative with the concentrations of the reactants or, if necessary, with the concentrations of the products.

The study of the change in the concentration of reagents over time under the conditions of the reaction of nucleophilic substitution showed that two cases are possible:

In the first case, the change in concentration is proportional only to the concentration of the substrate dc/dt = K[alkyl halide]

In the second case, the change in concentration is proportional to the concentration of the substrate and the concentration of the nucleophilic particle - dc/dt = K[alkyl halide]×[nucleophile]

The mechanism corresponding to the first case is called monomolecular nucleophilic substitution and is denoted S N 1 .

The mechanism corresponding to the second case is called bimolecular nucleophilic substitution and is denoted S N 2

1.4.2. Mechanism S N 1. Monomolecular substitution

By mechanism S N 1 e.g. hydrolysis tert-butyl bromide:

In the mechanism S N 1 distinguish the following stages:

At the first stage, the halogen derivative is ionized with the formation of a carbocation and a bromide ion. This stage is rate-limiting and is characterized by the highest activation energy:

The bromide ion forms hydrogen bonds with water molecules and is thereby stabilized. The resulting carbocation is also stabilized by solvent solvation. But more important is the stability of the carbocation itself. It must be stabilized by intramolecular electronic effects, the so-called. be tertiary or be in conjugation with the π-electron system (be resonantly stabilized).

At the second stage, the carbocation rapidly interacts with the nucleophile, in particular with water.