Nucleophilic addition reactions (reaction-AdN). Examples of nucleophilic addition reactions Reversibility of nucleophilic addition reactions

(reactions of addition-cleavage).

Reactions of nucleophilic substitution involving - hybridized carbon atom. Let us consider the mechanism of reactions of this type using the example of the interaction of carboxylic acids with alcohols ( esterification reaction). In the carboxyl group of the acid, p, -conjugation, since a pair of electrons of the oxygen atom of the OH hydroxyl group enters conjugation with a carbon-oxygen double bond (-bond):

Such conjugation is the cause, on the one hand, of increased acidity of carboxyl compounds, and on the other hand, a decrease in the partial positive charge () on the carbon atom of the carboxyl group (-hybridized atom), which greatly complicates the direct attack of the nucleophile. In order to increase the charge on the carbon atom, additional protonation is used - acid catalysis (stage I):

At stage II, the attack of the nucleophile (alcohol molecule), the protonation of the hydroxyl group with the formation of a well-leaving group occurs, at stage III - its elimination and at stage IV - proton regeneration - return of the catalyst with the formation of the final product - an ester. The reaction is reversible, which is observed during the hydrolysis of esters, the hydrolysis of fats in biosystems.

Reactions of nucleophilic addition. The most characteristic reactions of nucleophilic addition () for oxo compounds - aldehydes and ketones. The mechanism of these reactions has common features; it is a two-stage ionic process. The first stage (limiting) is a reversible attack by the nucleophile Nu : with the formation of the so-called tetrahedral intermediate. The second stage is a fast electrophile attack:

The reactivity of the oxo compound is influenced by the nature of the R and groups. Thus, the introduction of electron-donating substituents reduces the reactivity, while the introduction of electron-withdrawing substituents enhances it. Therefore, aldehydes are more reactive than ketones. In addition, the reactivity depends on the nature of the nucleophile. For example, RSH thiols, being stronger nucleophiles than ROH alcohols, react with both aldehydes and ketones, forming thioacetals resistant to hydrolysis, while acetals, the products of addition of alcohols to aldehydes, are not resistant to hydrolysis:

Please note that the last stages of the process represent the attack of the nucleophile (alcohol molecule) on the electrophilic reaction center (carbocation) and follow the mechanism of nucleophilic substitution. The resulting intermediate compounds - hemiacetals - are unstable. Their stabilization is possible only in a cyclic form during the formation of cyclic hemiacetals, for example, 5-hydroxypentanal:

Another example of a biologically important reaction of this type is the addition of amines and some other nitrogen-containing compounds to carbonyl compounds - aldehydes and ketones. The reaction goes along the mechanism of nucleophilic addition-elimination (-E), or nucleophilic addition-cleavage:

Other nitrogen-containing compounds that act as nucleophiles in these reactions: hydrazine, hydroxylamine, phenylhydrazine .

The products of the -E reactions in these cases are compounds of the general formula

called hydrazones (X = ), oximes (X = OH), phenylhydrazones (X = ), imines (X = R), which will be discussed in more detail in the relevant sections.

In addition to the indicated addition reactions, reactions are possible Ad R- free radical addition and polymerization or polycondensation.

Ad R - free radical addition

An example of a reaction polycondensation is the polycondensation of phenol with aldehydes, in particular, with formaldehyde, which results in the formation of polymeric reaction products - phenol-formaldehyde resins and solid polymers.

The interaction of phenol with formaldehyde can be described by the scheme:

In the course of further steps, a polymer is formed, and the by-product of the polycondensation reaction, in this case, is water.

CHAPTER 4. OXO COMPOUNDS (ALDEHYDES AND KETONES).

Questions for the lesson.

1. Electronic structure of the carbonyl group (>C=0) in oxo compounds.

2. Effect of substituents on the reactivity of >C=0-bonds in oxo compounds.

3. Mechanism of nucleophilic addition at the >C=0 bond.

4. Reactions of nucleophilic addition (for example, water, alcohols, sodium bisulfite, HCN).

5. Reactions of addition-elimination on the example of hydroxylamine, hydrazine, amines.

6. Disproportionation reaction using benzylaldehyde as an example.

7. Aldol condensation reaction mechanism.

8. Oxidation of aldehydes and ketones.

9. Polymerization of aldehydes.

Depending on the nature of the substituents associated with the carbonyl group, carbonyl compounds are divided into the following classes: aldehydes, ketones, carboxylic acids and their functional derivatives.

The chemistry of aldehydes and ketones is determined by the presence of a carbonyl group. This group, firstly, is the site of nucleophilic attack and, secondly, increases the acidity of the hydrogen atoms associated with the -carbon atom. Both of these effects are quite consistent with the structure of the carbonyl group, and in fact both are due to the ability of oxygen to take on a negative charge.

(In this chapter, only the simplest types of nucleophilic addition reactions are considered. In Chapter 27, reactions of -hydrogen atoms will also be discussed.)

The carbonyl group contains a carbon-oxygen double bond; since the mobile -electrons are strongly attracted to oxygen, the carbonyl group carbon is an electron-deficient center, and the carbonyl group oxygen is electron-rich. Since this part of the molecule is flat, it is relatively accessible to attack from above or below this plane in a direction perpendicular to it. Not surprisingly, this available polarized group is highly reactive.

What kind of reagents will attack such a group? Since the most important stage in these reactions is the formation of a bond with an electron-deficient (acidic) carbonyl carbon, the carbonyl group is most prone to interact with electron-rich nucleophilic reagents, i.e., with bases. Typical reactions of aldehydes and ketones would be nucleophilic addition reactions.

As expected, the most accurate picture of the reactivity of the carbonyl group can be obtained by considering the transition state for the addition of a nucleophile. The carbon atom in the reagent is trigonal. In the transition state, the carbon atom begins to assume the tetrahedral configuration it will have in the product; thus, the groups associated with it converge somewhat. Therefore, some spatial difficulties can be expected, i.e., large groups will prevent this approach to a greater extent than smaller groups. But the transition state in this reaction will be relatively less difficult than the transition state for, say, a -reaction in which carbon is bonded to five atoms. It is this relative ease that is meant when the carbonyl group is said to be available for attack.

In the transition state, oxygen begins to acquire electrons and the negative charge that it will have in the final product. It is the tendency of oxygen to acquire electrons, or rather its ability to carry a negative charge, that is the real reason for the reactivity of the carbonyl group towards nucleophiles. (The polarity of the carbonyl group is not the cause of reactivity, but only another manifestation of the electronegativity of oxygen.)

Aldehydes tend to undergo nucleophilic addition more easily than ketones. This difference in reactivity is consistent with the nature of the intermediate state of the reaction and, apparently, is explained by the combined action of electronic and spatial factors. The ketone contains a second alkyl or aryl group, while the aldehyde contains a hydrogen atom. The second aryl or alkyl group of the ketone is larger than the hydrogen atom of the aldehyde and will therefore be more resistant to increasing steric hindrance in the transition state. The alkyl group donates electrons and thereby destabilizes the transition state by increasing the negative charge on the oxygen.

One might expect that the aryl group, with its electron-retracting inductive effect (problem 18.7, p. 572), would stabilize the transition state and thereby speed up the reaction; however, apparently, this effect stabilizes the initial ketone to an even greater extent due to resonance (contribution of structure I) and, as a result, deactivates the ketone in the reaction under consideration.

Scheme:

Mechanism:

1- Education π-complex (slow)

2- Education ϭ-complex or carbocation (slow)

Carbocations are positively charged unstable intermediates with a sextet of valence electrons at the carbon atom.

Nucleophilic attack of the halogenonium ion (fast)

The rate of the reaction essentially depends on the structure of the alkene. When methyl substituents are introduced into the alkene, the electron density increases due to +I CH 3 and the reaction rate increases. On the other hand, the trifluoromethyl group CF 3, due to the negative inductive effect, lowers the electron density in the alkene and thus makes the electrophilic attack more difficult.

CF3CH=CH2< CH 2 =CH 2 < CH 3 CH=CH 2 < (CH 3) 2 CH=CH 2 < (CH 3) 2 CH=CH(CH 3) 2

Increasing the rate of reaction of alkenes with halogens.

When water is added to the unsaturated hydrocarbon, a fourth stage (catalyst return) is added to the mechanism.

47-reaction of electrophilic substitution: heterolytic reaction involving the π-electron cloud of the aromatic system (halogenation, nitration, alkination).

S E -reaction of electrophilic substitution..

The interaction of arenes with the electrophilic aggregate also proceeds in stages through the formation of ϭ and π-complexes.

A characteristic feature of aromatic compounds of the benzene series, fused and heterocyclic aromatic compounds is their tendency to enter into reactions that do not lead to disruption of the aromatic system - the reaction substitution. On the contrary, in reactions that violate aromaticity, such as addition or oxidation, aromatic compounds have a reduced reactivity.

Scheme:

Mechanism:

Generation of an electrophilic particle.

2. Formation of a π-complex (slow)

3. Formation of a ϭ-complex or carbocation

4. Elimination of a proton from the ϭ-complex

Halogenation.

Nitration.

Alkynization.

48-Reaction of nucleophilic substitution at the sp 3 -hybridized carbon atom: heterolytic reactions due to the polarization of the ϭ-bond carbon-heteroatom (halogen derivatives, alcohols).

SN-Nucleophilic substitution reaction

SN are most characteristic of saturated organic compounds containing the following functional groups: halogen, hydroxyl, thiol and amino groups.

SN 1 - characteristic characteristic of tertiary and partially secondary alkane halides in the presence of a weak nucleophile and a polar solvent

Mechanism:

I stage

II stage

SN 2-characteristic of primary and partially secondary atoms.

Mechanism:

49-Nucleophilic addition reaction: heterolytic reaction involving carbon-oxygen π-bond (reaction of aldehydes and ketones with alcohols, primary amines). Influence of electronic and spatial factors, the role of acid catalysis. Biological significance of the nucleophilic addition reaction.

A N - Nucleophilic addition reaction.

characteristic of aldehydes and ketones.

Great importance in biologically has a reaction of carbonyl compounds (aldehydes and ketones) with ammonia, with the formation of imines (Schiff bases), very unstable, easily hydrolyzed compounds.

Imines are intermediates in some enzymatic reactions in the synthesis of amines from aldehydes and ketones.

For example, some α-amino acids are synthesized in the body according to this scheme.

The interaction of ammonia with aldehydes can be complicated by possible cyclization. So, from formaldehyde A.M. Butlerov was the first to receive a medical preparation - hexamethylenetetraamine (urotropin), which was widely used as an antiseptic.

acid catalysis serves to activate the substrate.

reaction centers.

Mechanism:

In reactions A N a catalyst (inorganic acid) is used to increase the reaction rate

Scheme:

Mechanism:

a) Interaction with alcohols. Aldehydes can react with one or two alcohol molecules to form hemiacetals and acetals, respectively.

Hemiacetals are compounds containing both hydroxyl and alkoxyl (OR) groups at one carbon atom. Acetals are compounds containing two alkoxy groups at one carbon atom:

hemiacetal acetal

The reaction for obtaining acetals is widely used in organic syntheses to "protect" the active aldehyde group from undesirable reactions:

Such reactions are of particular importance in the chemistry of carbohydrates.

b) Accession of hydrosulfites serves to isolate aldehydes from mixtures with other substances and to obtain them in pure form, since the resulting sulfo derivative is very easily hydrolyzed:

R-CH \u003d O + NaHSO 3 → R-CH (OH) -SO 3 Na.

in) reaction with theoli. aldehydes and ketones react with thiols in an acidic environment, dithioacetal is formed:

G) Accession of hydrocyanic(hydrocyanic) acid:

CH 3 -CH \u003d O + H-CN → CH 3 -CH (CN) -OH.

The resulting compound contains one carbon atom more than the original aldehyde or ketone, so these reactions are used to lengthen the carbon chain.

e) Attachment of the Grignard reagent. In organic synthesis, the Grignard reagent is extremely often used - one of the simplest organometallic compounds.

When a solution of a haloalkane in diethyl ether is added to magnesium shavings, an exothermic reaction easily occurs, magnesium goes into solution and a Grignard reagent is formed:

R-X + Mg → R-Mg-X,

where R is an alkyl or aryl radical, X is a halogen.

- The interaction of the Grignard reagent with formaldehyde, almost any primary alcohol (except methanol) can be obtained. For this, the addition product of the Grignard reagent is hydrolyzed with water.

H 2 CO + RMgX → R-CH 2 -O-MgX → R-CH 2 -OH.

- When using any other aliphatic aldehydes, secondary alcohols can be obtained:

- Tertiary alcohols are obtained by the interaction of Grignard reagents with ketones:

(CH 3) 2 C \u003d O + R-MgX → (CH 3) 2 C (R) -O-MgX → (CH 3) 2 C (R) -OH

16. Aldehydes and ketones. Chemical properties: condensation reaction, reactions with nitrogen-containing compounds. Individual representatives and their application.

Organic compounds in the molecule of which there is a carbonyl group C=O are called carbonyl compounds or oxo compounds. They are divided into two related groups - aldehydes and kwtons.

Condensation reaction:

Aldol condensation

with compounds with CH acidic properties, aldehydes and ketones are able to enter into various condensation reactions. compounds containing mobile hydrogen in these reactions acts as a nucleophilic reagent and is called the mytelin component, and aldehydes and ketones are called the carbonyl component. the reaction of aldol condensation proceeds under the action of dilute alkalis on the aldehyde or ketone. while one aldehyde molecule is a methylene component, the other is a carboxylic component.

Under the action of a base, the aldehyde removes a proton from the α CH acid center and turns into a carbanion. The carbanion is a strong nucleophile and attaches to another aldehyde molecule. the stabilization of the resulting anion occurs due to the elimination of a proton from a weak acid.

Mechanism:

If the aldol condensation is accompanied by the elimination of water (at high temperature), then such a condensation is called crotonic condensation:

The reaction of aldol or cratonic condensation is often carried out in a mixed substance. when the methylene and carboxylic components are different compounds. the selection of partners for this reaction is based on the fact that the carbonyl component must be highly reactive in nucleophilic addition reactions. basically it's an aldehyde. at the same time, the methylene component must have a high CH-acidity - various aldehydes or ketones having an α-hydrogen atom.

Nucleophilic addition reactions - addition reactions in which the attack at the initial stage is carried out by a nucleophile - a particle that is negatively charged or has a free electron pair.

In the final step, the resulting carbanion undergoes electrophilic attack.

Despite the commonality of the mechanism, addition reactions are distinguished by carbon-carbon and carbon-heteroatom bonds.

Nucleophilic addition reactions are more common for triple bonds than for double bonds.

Nucleophilic addition reactions at carbon-carbon bonds

Multiple bond nucleophilic addition is usually a two-step Ad N 2 process - a bimolecular nucleophilic addition reaction:

Nucleophilic addition at the C=C bond is quite rare, and, as a rule, if the compound contains electron-withdrawing substituents. The Michael reaction is of the greatest importance in this class:

Attachment at the triple bond is similar to attachment at the C=C bond:

Nucleophilic addition reactions at a carbon-heteroatom bond Nucleophilic addition at a multiple carbon-heteroatom bond has the Ad N 2 mechanism

As a rule, the rate-limiting stage of the process is a nucleophilic attack, electrophilic addition occurs quickly.

Sometimes the addition products enter into an elimination reaction, thereby collectively giving a substitution reaction:

Nucleophilic addition at the C=O bond is very common, which is of great practical, industrial and laboratory importance.

Acylation of unsaturated ketones

This method involves treating the substrate with an aldehyde and cyanide ion in a polar aprotic solvent such as DMF or Me 2 SO. This method is applicable to a,b-unsaturated ketones, esters and nitriles.

Condensation of esters with ketones

When esters are condensed with ketones, the yield of α-diketone is low, about 40%, this is due to the side reaction of ester self-condensation.

Hydrolysis of nitro compounds (Nef reaction)

The Nef reaction is a reaction of acid hydrolysis of nitro compounds with the formation of carbonyl compounds. Discovered in 1892 by the Russian chemist M.I. Konovalov and J. Nef in 1894. The Nef reaction consists in the hydrolysis of acyl forms of nitro compounds (nitronic acids), and therefore primary and secondary aliphatic and alicyclic nitro compounds can enter into it.

The Nef reaction makes it possible to obtain dicarbonyl compounds with a yield of up to 80-85%. To do this, the reaction is carried out at pH=1, since in a less acidic medium, nitronic acids isomerize back into a nitro compound with a decrease in the conversion of the nitro compound, and in a more acidic one, the formation of by-products increases. This reaction is carried out at t=0-5 0 C .

Interaction of ketones with acid chlorides in the presence of piperidine

Acid chlorides are easily reduced to primary alcohols under the action of lithium aluminum hydride. But if the enamine obtained from the ketone under the action of piperidine is reacted with acid chlorides, then after the hydrolysis of the initially obtained salt, b-diketones are formed.