Primary and secondary amines react with acid halides, anhydrides and carboxylic acid esters to form amides. All these reactions should be classified as nucleophilic substitution at the carbonyl sp 2 -hybrid carbon atom, their mechanism and application in the synthesis of amides are discussed in Chapter 18.

21.6.3 Reaction of primary and secondary amines with carbonyl compounds. Obtaining imines and enamines,

Aldehydes and ketones react with primary and secondary amines to form imines and enamines, respectively (see chapter 16).

These reactions should be considered as nucleophilic addition at the carbonyl group.

21.6.4 Reaction of amines with sulfonyl halides. Hinsberg test

Primary and secondary amines react with sulfonyl halides to form sulfonamides.

The mechanism for the formation of sulfamides is similar to the production of amides from acyl halides and amines. The production of sulfonamides forms the basis of the universal test for primary, secondary and tertiary amines. This simple and very affordable method for the recognition of amines was proposed in 1890 by Hinsberg and is called the Hinsberg test. A mixture of the test amine and benzenesulfochloride С 6 Н 5 SO 2 Сl or NSα-toluenesulfochloride is shaken with an excess of cold aqueous sodium hydroxide solution. After 10-15 minutes, the mixture is acidified to a pronounced acidic reaction. Primary, secondary and tertiary amines behave differently in this two-step process. Primary amines react with benzenesulfonyl chloride to give N-substituted sulfonamides, which contain a sufficiently "acidic" hydrogen atom at the nitrogen atom, and dissolve in aqueous alkali to form a homogeneous solution of the sodium salt of sulfamide. On acidification, the water-insoluble N-substituted sulfamide precipitates from this solution.

Secondary amines react with benzenesulfochloride in aqueous alkali to form N, N-disubstituted sulfamide. It is insoluble in aqueous alkali; does not contain an acidic hydrogen atom with nitrogen. Acidification of the reaction mixture in this case does not cause any external changes - N, N-disubstituted sulfamide remains in the form of a precipitate.

A tertiary amine insoluble in water does not undergo changes when treated with an aqueous alkali solution, the initially ionic N-benzenesulfonyl-N, N-trialkylammonium chloride formed is split under the action of a hydroxide ion to sodium benzenesulfonate and a tertiary amine:

Upon acidification of the reaction mixture, the tertiary amine dissolves due to the formation of a water-soluble salt

Sulfonamides found use in chemotherapy after it was discovered in 1935 that sulfanilic acid amide NS-NH 2 C 6 H 4 SO 2 NH 2 has a strong anti-streptococcal effect. This discovery, extremely important for modern medicine and chemotherapy, was made quite by accident. His story is briefly as follows. The daughter of one of the employees of a large company that produces azo dyes, as a result of a pinprick, introduced a streptococcal infection. She was almost doomed when her father at random risked giving her a dose of prontosil - one of the dyes produced by his company. Prontosil was previously successfully tested in mice, where it suppressed the growth of streptococci. After a short time, the girl fully recovered from her illness, which prompted E. Fourno at the Pasteur Institute in Paris to tackle this miraculous problem. Fourno discovered that in the human body, prontosil, called red streptocid, is cleaved by enzymes to NS-aminobenzenesulfamide, which is a true active principle against various streptococci, pneumococci and gonococci. Sulfanilic acid amide received the name of the drug white streptocid.

This discovery triggered an avalanche-like stream of studies on the activity of various pair-aminobenzenesulfonamides, differing only in the nature of the substituent X in NS-NH 2 C 6 H 4 SO 2 NHX. Of the approximately ten thousand such synthetic derivatives, less than thirty have entered medical practice. Among them are the well-known drugs by their trade names sulfidine, norsulfazole, sulfadimezine, etazole, sulfadimethoxine, phthalazole, etc. Some of them were obtained before the Second World War and saved the lives of hundreds of thousands of people who underwent inflammatory processes caused by pneumococci and streptococci after being wounded ... Below are some of the modern sulfa drugs.

Sulfonamide preparations are prepared according to the following typical scheme:

All these drugs are like "miraculous bullet" (the term was introduced by the founder of chemotherapy P. Ehrlich) accurately infect bacteria and do not harm living cells.

Although the mechanism of action of drugs in most cases is not known in detail, sulfanilamide is a rare exception. Sulfanilamide kills bacteria by participating in the biosynthesis of folic acid. Folic acid synthesis is extremely important for the vital activity of bacteria. Animal cells themselves are not able to synthesize folic acid, but it is a necessary component in their "diet". This is why sulfonamide is toxic to bacteria but not to humans.

Folic acid can be represented as consisting of three fragments - a derivative of pteridine, a molecule pairα-aminobenzoic acid and glutamic acid (a very common amino acid). Sulfanilamide interferes with the biosynthesis of folic acid, competing with pair-aminobenzoic acid for the inclusion of folic acid in the molecule. By its structure and size, sulfonamide and NSα-aminobenzoic acid are very close (Figure 21.1), which allows the sulfanilamide molecule to "mislead" the enzymes responsible for binding all three parts of the folic acid molecule. Thus, sulfanilamide takes place pairα-aminobenzoic acid in the "false" folic acid molecule, which is unable to fulfill the vital functions of true folic acid inside the bacterium. This is the secret of the antibacterial activity of sulfanilamide and its structural analogs.

Rice. 21.1. Structural similarity pairα-aminobenzoic acid and sulfonamide

The discovery of the mechanism of action of sulfonamide led to the discovery of many other new antimetabolites. One of them is methotrexate, which has a pronounced antitumor activity. It is easy to see its close structural analogy with folic acid.

Primary and secondary alkyl halides react with ammonia to form primary amines. Most often, the reaction proceeds according to the mechanism Primary amine (1) can react with another halogen-alkene molecule, giving a secondary amine. Similarly, secondary amines can be converted into tertiary amines (III). And finally, tertiary amines give ionic compounds with haloalkanes, which are called quaternary ammonium salts (IV). This sequence of reactions is shown below:

Thus, it is possible to obtain primary, secondary and tertiary amines, as well as quaternary salts, using the appropriate amount of haloalkane. In the synthesis of amines, salts are initially formed, which must be neutralized to obtain the free amine. The general scheme of such a synthesis is as follows:

Further, in the equations of reactions, we will not depict the formation of salt, but will immediately write the formula of the final amine. The following examples illustrate the fact that a wide variety of amines can be prepared by varying the number of moles and the nature of the haloalkanes:

Recovery of amtsda and nitriles

Strong reducing agents, such as lithium aluminum hydride, reduce amides to amines, converting a carbonyl group into a group.Thus, you can obtain primary, secondary and tertiary amines, including aromatic ones:

Primary amines can be synthesized by catalytic hydrogenation of nitriles, which, as you remember, are obtained from haloalkanes and cyanides:

For example:

Aromatic amines (substituted anilines) can be conveniently obtained from the corresponding nitro compounds by reducing them with iron or tin in the presence of hydrochloric acid. Methods for obtaining aromatic nitro compounds and their reduction have already been discussed in Ch. nine.

The aromatic amines obtained in this way can be alkylated at the nitrogen atom in the same way as other amines:

Amines are prepared by alkylation of ammonia with haloalkanes using different ratios of reagents. The reduction of amides and nitriles is also used. Aromatic amines are prepared by reduction of the corresponding nitro compounds.

1. Synthesis from alcohols. Passing vapors of alcohol and ammonia at 400 0 C over the catalyst, a mixture of primary, secondary and tertiary alcohols is obtained:

2. Hoffmann's reaction. The action of ammonia on halogenated derivatives makes it possible to obtain a mixture of salts of various amines:

3. Zinin's reaction. Nitro compounds are reduced with hydrogen in the presence of a catalyst:

4. Recovery of nitriles:

5. Synthesis from acid amides:

6. Interaction of chlorobenzene with ammonia:

Acid-base properties of amines. Amines have pronounced basic properties. These are typical bases according to Bronsted's theory, according to which structures that tend to attach a proton belong to the bases. In the series of aliphatic amines, the basic properties of the tertiary amine are more pronounced, which is explained by the donor induction effect of alkyl groups (R), which increases the electron density on nitrogen and the ability of nitrogen to attach a proton is more pronounced.

Among aromatic amines, aniline has more pronounced basic properties and the following sequence is observed:

Chemical properties. Chemically, amines are very similar to ammonia and enter into various reactions as nucleophilic reagents. Typical amine reactions are amino group reactions.

1. Connection of hydrogen chloride:

2. Water connection:

3. Alkylation:

4. Acelation reaction:

5. Reaction of diazotization:

Cooled solutions of diazo salts are used to obtain azo dyes. Phenols or aromatic amines are used as an azo component in azo coupling reactions.

Azo coupling reaction:

The azo coupling reaction can be considered as an electrophilic substitution reaction in the aromatic benzene ring. The diazocation acts as an electrophilic particle, and the substitution proceeds predominantly in the para-position.

The resulting product is a dye. Dyes are organic compounds that are colored and capable of dyeing various fabrics. Dyes must necessarily contain in their composition chromoform groups:

and have high degree conjugation in a molecule.

In order for the dye to bind to the fabric, it must contain auxochromic groups: OH, NH 2, CH 3.

Amines- these are organic compounds in which a hydrogen atom (maybe more than one) is replaced by a hydrocarbon radical. All amines are divided into:

• primary amines;
• secondary amines;
• tertiary amines.

There are also analogues of ammonium salts - quaternary salts of the type [ R 4 N] + Cl - .

Depending on the type of radical amines may be:

• aliphatic amines;
• aromatic (mixed) amines.

Aliphatic limit amines.

General formula C n H 2 n +3 N.

The structure of amines.

The nitrogen atom is in sp 3 -hybridization. In the 4th non-hybrid orbital there is a lone pair of electrons, which determines the main properties of amines:

Electron-donor substituents increase the electron density on the nitrogen atom and enhance the basic properties of amines; for this reason, secondary amines are stronger bases than primary ones, because 2 radicals at the nitrogen atom create a higher electron density than 1.

In tertiary atoms plays important role spatial factor: because 3 radicals obscure the lone pair of nitrogen, which is difficult to "approach" to other reagents, the basicity of such amines is lower than that of primary or secondary ones.

Isomerism of amines.

For amines, isomerism of the carbon skeleton is characteristic, isomerism of the position of the amino group:

What are the amines?

The name usually lists hydrocarbon radicals (in alphabetical order) and adds the ending -amine:

Physical properties of amines.

The first 3 amines are gases, the middle members of the aliphatic series are liquids, and the higher ones are solids... The boiling point of amines is higher than that of the corresponding hydrocarbons, because in the liquid phase, hydrogen bonds are formed in the molecule.

Amines are readily soluble in water; as the hydrocarbon radical grows, the solubility decreases.

Getting amines.

1. Alkylation of ammonia (main method), which occurs when an alkyl halide is heated with ammonia:

If the alkyl halide is in excess, then the primary amine can undergo an alkylation reaction, turning into a secondary or tertiary amine:

2. Recovery of nitro compounds:

Use ammonium sulfide ( Zinin reaction), zinc or iron in an acidic medium, aluminum in an alkaline medium, or hydrogen in the gas phase.

3. Recovery of nitriles. Use LiAlH 4:

4. Enzymatic decarboxylation of amino acids:

Chemical properties of amines.

Everything amines- strong bases, moreover, aliphatic ones are stronger than ammonia.

Aqueous solutions are alkaline.

abstract

Synthesis of amines from alcohols

Introduction 3

1. Characteristics of alkylation processes 4

2. Chemistry and theoretical foundations of the process 10

3. Process technology 13

References 16

Introduction

Alkylation refers to the processes of introducing alkyl groups into the molecules of organic and some inorganic substances. These reactions are very practical significance for the synthesis of aromatic compounds alkylated in the nucleus, isoparaffins, many mercaptans and sulfides, amines, substances with an ether bond, element - and organometallic compounds, products of processing - oxides and acetylene. Alkylation processes are often intermediate steps in the production of monomers, detergents, etc.

Many of the alkylation products are produced on a very large scale. For example, in the United States annually synthesize about 4 million tons of ethylbenzene, 1.6 million tons of isopropylbenzene, 0.4 million tons of higher alkylbenzenes, over 4 million tons of glycols and other products of alkylene oxide processing, about 30 million tons of isoparaffinic alkylate, about 1 million tons of tert-butyl methyl ether, etc.

1. Characteristics of alkylation processes

1. Classification of alkylation reactions

The most rational classification of alkylation processes is based on the type of newly formed bond.

Alkylation at a carbon atom (C-alkylation) consists in the substitution of an alkyl group for a hydrogen atom located on a carbon atom. Paraffins are capable of this substitution, but alkylation is most typical for aromatic compounds (Friedel-Crafts reaction):

https://pandia.ru/text/78/129/images/image003_92.gif "width =" 221 "height =" 23 src = ">

Alkylation at oxygen and sulfur atoms (O - and S-alkylation) is a reaction in which an alkyl group is bonded to an oxygen or sulfur atom:

ArOH + RCI ArOH + NaCI + H2O

NaSH + RCI → RSH + NaCI

In this case, too general definition Alkylation also includes such processes as hydrolysis of chlorine derivatives or hydration of olefins, and this shows that alkylation should be called only those reactions of introducing an alkyl group that do not have other, more essential and defining classification features.

Alkylation at the nitrogen atom (N-alkylation) consists in the replacement of hydrogen atoms in ammonia or amines with alkyl groups. This is the most important of the methods for the synthesis of amines:

ROH + NH3 → RNH2 + H2O

As in the case of hydrolysis and hydration reactions, N-alkylation is often classified as ammonolysis (or aminolysis) of organic compounds).

Alkylation at the atoms of other elements (Si-, Pb-, AI-alkylation) is the most important way to obtain element - and organometallic compounds, when the alkyl group is directly linked to the heteroatom:

2RCI + Si R2SiCI2

4C2H5CI + 4PbNa → Pb (C2H5) 4 + 4NaCI + 3Pb

3C3H6 + AI + 1.5H2 → Al (C3H7) 3

Another classification of alkylation reactions is based on differences in the structure of the alkyl group introduced into an organic or inorganic compound. It can be saturated aliphatic (ethyl and isopropyl) or cyclic. In the latter case, the reaction is sometimes called cycloalkylation:

https://pandia.ru/text/78/129/images/image007_43.gif "width =" 61 "height =" 26 "> ROCH = CH2

CH3-COOH + CH≡CH CH3-COO-CH = CH2

Finally, alkyl groups can contain various substituents, for example, chlorine atoms, hydroxy-, carboxy-, sulfonic acid groups:

C6H5ONa + CICH2-COONa → C6H5O-CH2-COONa + NaCI

ROH + HOCH2-CH2SO2ONa → ROCH2 – CH2SO2ONa + H2O

The most important of the reactions for the introduction of substituted alkyl groups is the process https://pandia.ru/text/78/129/images/image010_34.gif "width =" 563 "height =" 53 src = ">

2. Alkylating agents and catalysts

All alkylating agents by the type of bond that breaks in them during alkylation, it is advisable to divide into the following groups:

1..gif "width =" 260 "height =" 38 src = ">

This means that the lengthening and branching of the chain of carbon atoms in the olefin significantly increases its ability to alkylate:

CH2 = CH2< CH3-CH=CH2 < CH3-CH2-CH=CH2 < (CH3)2C=CH2

In some cases, alkylation with olefins proceeds under the influence of initiators of radical-chain reactions, illumination, or high temperature. Here, the intermediate active particles are free radicals. The reactivity of different olefins in such reactions is much closer.

Chlorine derivatives are the widest range of alkylating agents. They are suitable for C-, O-, S - and N-alkylation and for the synthesis of most elemental and organometallic compounds. The use of chlorine derivatives is rational for those processes in which they cannot be replaced by olefins or when chlorine derivatives are cheaper and more accessible than olefins.

The alkylating effect of chlorine derivatives is manifested in three different types interactions: in electrophilic reactions, in nucleophilic substitution and in free radical processes. The mechanism of electrophilic substitution is characteristic of alkylation at the carbon atom, but, unlike olefins, reactions are catalyzed only by aprotic acids (aluminum and iron chlorides). In the limiting case, the process proceeds with the intermediate formation of a carbocation:

https://pandia.ru/text/78/129/images/image014_29.gif "width =" 318 "height =" 26 src = ">

In another type of reaction, characteristic of alkylation at oxygen, sulfur and nitrogen atoms, the process consists in nucleophilic substitution of the chlorine atom. The mechanism is similar to the hydrolysis of chlorine derivatives, and the reaction proceeds in the absence of catalysts:

https://pandia.ru/text/78/129/images/image016_28.gif "height =" 25 "> → 4NaCI + Pb (C2H5) 4 + 3Pb

Alcohols and ethers are capable of C-, O-, N- and S-alkylation reactions. The ethers also include olefin oxides, which are internal ethers of glycols, and of all ethers, only olefin oxides are practically used as alkylating agents. Alcohols are used for O - and N-alkylation in cases where they are cheaper and more accessible than chlorine derivatives. To break their alkyl-oxygen bond, acid-type catalysts are required:

R-OH + H + ↔ R-OH2 ↔ R + + H2O

3. Energy characteristics of the main alkylation reactions

Depending on the alkylating agent and the type of the breaking bond in the alkylated substance, the alkylation processes have very different energy characteristics. The values ​​of thermal effects for the gaseous state of all substances in some important processes of alkylation at C-, O - and N-bonds are shown in Table 1. Since they significantly depend on the structure of alkylating substances, the table lists the most common ranges of variation in thermal effects.

Table 1

Heat effect of critical alkylation reactions

From a comparison of the data presented, it can be seen that when the same alkylating agent is used, the heat of reaction during alkylation at different atoms decreases in the following order Cap> Salif> N> O, and for different alkylating agents it changes as follows:

https://pandia.ru/text/78/129/images/image020_18.gif "width =" 161 "height =" 28 src = "> giving high value equilibrium constants at all permissible temperatures. In contrast, the interaction of phenols with ammonia and amines is reversible:

ArOH + NH3 ↔ ArNH2 + H2O

In the overwhelming majority of cases, alcohols react with ammonia and amines only in the presence of catalysts. To obtain methylanilines from aniline and methanol, sulfuric acid is used:

Ammonium "href =" / text / category / ammonij / "rel =" bookmark "> ammonium. The action of heterogeneous catalysts is to activate the C - O bond in alcohol due to chemisorption at their acid sites:

https://pandia.ru/text/78/129/images/image024_17.gif "width =" 206 "height =" 30 src = ">

https://pandia.ru/text/78/129/images/image026_14.gif "width =" 390 "height =" 53 src = ">

In this case, the ratio of the rate constants of the successive stages of the reaction is unfavorable for the production of the primary amine, since ammonia is more weak basis and a nucleophilic reagent. The same acid-type catalysts cause intermolecular migration of alkyl groups, similar to the previously occurring reaction of transalkylation of aromatic compounds under the influence of AICI3. Thus, reversible amine transalkylation reactions occur:

2RNH2 ↔ R2NH + NH3

2R2NH ↔ RNH2 + R3N

strongly affecting the composition of the alkylation products. At the same time, the equilibrium ratios are much more than kinetic, favorable for the production of the primary amine.

Although in practical conditions the equilibrium is not fully achieved, it is still possible to use a relatively small excess of ammonia, which reduces the cost of its regeneration. If the target product of the process is a secondary amine, then by returning the primary and tertiary amines to the reaction, it is possible to completely exclude their formation by directing the process only in the desired direction. In this case, stationary concentrations of by-products are established in the reaction mass, corresponding to the conditions of equality of the rates of their formation and consumption.

To carry out the reaction between ammonia and alcohols, dehydrogenating catalysts (copper, nickel, cobalt, supported on alumina) can also be used. In this case, the reaction mechanism is completely different - first, the alcohol is dehydrogenated to an aldehyde, and then the aldehyde condenses with ammonia and the resulting imine is hydrogenated:

Mixers "href =" / text / category / smesiteli / "rel =" bookmark "> mixer 1 and are fed to heat exchanger 2, where they are vaporized and heated with hot reaction gases. In reactor 3, the reactions described above proceed and amines are formed at almost complete conversion The hot gases give up their heat to the initial mixture in the heat exchanger 2 and are sent for further processing.

The resulting products are separated by multistage rectification; at each stage, a pressure is created to obtain reflux by cooling with water. First of all, in column 4, the most volatile ammonia is distilled off, which is recycled. Bottom liquid enters the extractive distillation column 5 with water (in the presence of water, the relative volatility of trimethylamine becomes the highest in comparison with other) methylamines. The trimethylamine (TMA) distilled off during this process can be partially taken in the form of a commercial product, but its main amount is sent for recycling. For the other two amines, the boiling points differ more (6.8 and 7.40C), and they can be separated by conventional rectification in columns 6 (monomethylamine, MMA) and 7 (dimethylamine, DMA). Each of them from the top of the column can be taken as a commercial product or partially (or completely) sent for recycling.

Finally, in the column 8, unconverted methanol is distilled off from the waste water and returned to the reaction. The total yield of amines, taking into account all losses, reaches 95%.

In the synthesis of ethylamines, the stage of preparation of the initial mixture and the reaction unit are performed similarly to those shown in Fig. 1. Separation of amines is facilitated by a larger difference in boiling points (16.5, 55.9 and 89.50) and is achieved by conventional rectification with successive distillation of ammonia, mono-, di - and triethylamines. In this case, the by-product is ethylene, which is removed from the system during the condensation of the mixture for stripping off ammonia.

Petrochemicals "href =" / text / category / neftehimiya / "rel =" bookmark "> petrochemical
synthesis. M., Chemistry. 1988. - 592 p .;

4., Vishnyakova of petrochemical synthesis. M., 1973. - 448 p .;

5. Yukelson basic organic synthesis. M., "Chemistry", 1968.