Department of Chemistry, St. Paul's C. M. College

Lecture note for CC-4-8 (Organic Chemistry-4)

Series: Nitrogen Compounds

Aliphatic Amines-I

Synthesis of aliphatic amines:

Let us consider the synthesis of the primary amine R-NH2. Forming a C-N (carbon-heteroatom) bond is easier than forming a C-C bond. So we may consider the following type of disconnections.

Thus a primary amine may be obtained by the treatment with ethanolic NH3 on an alkyl halide.

But the reaction does not follow the above course absolutely. Over-alkylation is a serious problem:

+ and so on, i.e. after alkali treatment we get a mixture of RNH2, R2NH, R3N and R4N . But we do want the primary amine RNH2 exclusively. How may we do it? o Separation of primary amine from the above mixture – Hinsberg method.

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Lecture note prepared by Kaushik Basu, St. Paul’s C. M. College, Kolkata

o As evident from the above scheme, here NH3, RNH2, R2NH, and R3N are in competition to react with RX. If NH3 acts as the nucleophile in preference over the other nucleophilic species, we may get the primary amine. So we have to use a large excess of NH3. Thus we have the following ways to obtain amino acids:

o We have to use a masked form of ammonia in which two valences of nitrogen are satisfied by easily removable groups, i.e.

Thus we have the Gabriel’s phthalimide synthesis. But phthalimide cannot act as a nucleophile as shown:Department of Chemistry, St. Paul's C. M. College

This is due to the fact that the nucleophilicity of nitrogen in phthalimide is seriously diminished because of the presence of two electron withdrawing carbonyl groups. How can we solve this problem? Note carefully that in phthalimide the hydrogen that is attached to the nitrogen heteroatom is doubly activated 2 by the two neighbouring carbonyl groups and is therefore very acidic in nature (pKa 8.3). Thus, Page

Lecture note prepared by Kaushik Basu, St. Paul’s C. M. College, Kolkata

Let us consider the synthesis of the following primary amine

We may consider the following retrosynthetic approach:

ThusDepartment the synthesis involves of the Chemistry,following steps: St. Paul's C. M. College

The acidic or alkaline hydrolysis of N-alkyl phthalimide is a slow reaction. However, the primary amine

can be released from N-alkyl phthalimide more efficiently by the treatment with hydrazine hydrate.

Consider the two approaches: 3 Page

Lecture note prepared by Kaushik Basu, St. Paul’s C. M. College, Kolkata

A) Alkaline hydrolysis of N-alkylphthalimide:

B) Hydrazinolysis of N-alkylphthalimide:

Hydrazinolysis of N-alkylphthalimide proceeds more easily than hydrolysis of the same, because o Hydrazinolysis is entropically more favourable than hydrolysis as the second step for the former is intramolecular in nature. o Hydrazine is more nucleophilic in nature because of the α-effect.

Representative examples:

1. Synthesis of glycine:

Retrosynthetic analysis:

Forward synthesis:

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1. Synthesis of t-butylamine:

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Lecture note prepared by Kaushik Basu, St. Paul’s C. M. College, Kolkata

Retrosynthetic analysis: Following the analogy behind Gabriel’s phthalimide method:

However, with a tertiary amine, elimination takes over:

How can we solve this problem? Recall that compounds containing the t-butyl group can be accessed via the Pinacol-Pinacolone rearrangement. Thus,

An alternative route makes use of Ritter reaction:

Yet another alternative makes use of the acidity of the nitromethane to alkylate the methyl carbon of the same, followed by reduction of nitro to amine:

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Following the last protocol, one can synthesise

Another masked form of ammonia in which two valences of nitrogen are satisfied by easily removable 5 groups is the azide ion: Page

Lecture note prepared by Kaushik Basu, St. Paul’s C. M. College, Kolkata

For example:

By analogy with the synthesis of primary amine using phthalimide or sodium azide, we can say that to access secondary amines we have to use a derivative of NH3 in which any one valence of nitrogen is satisfied by an easily removable group. Thus we have the following two techniques:

By using the above two methods we can obtain secondary amines that contain two same alkyl groups on nitrogen,Department avoiding the problem of Chemistry, of over-alkylation .St. Paul's C. M. College Let us consider the synthesis of secondary and tertiary amines. At a first glance it appears that these amines may be obtained by alkylating the primary and secondary amines respectively with an alkyl halide. However, this approach is only useful in cases where the product is less nucleophilic than the starting material (for electronic or steric reasons) or if the alkylation is intramolecular in nature. Thus,

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Lecture note prepared by Kaushik Basu, St. Paul’s C. M. College, Kolkata

Here the product (a secondary amine) is less nucleophilic than the starting material (methylamine) due to the electron withdrawing –I effect of the neighbouring carbonyl group. Another example,

Here the product (a tertiary amine) is less nucleophilic than the starting material (a secondary amine) due to the –I effect of the neighbouring carbonyl group and also due to steric crowding in the tertiary amine. Let us consider the following example:

The final product is formed here through an intramolecular reaction which is much faster and more favourable than the competing intermolecular reaction.

Thus, unless there is a specific reason for the success of the reaction – the alkylation of amine by using an alkyl halide, we have to avoid it lest over-alkylation intervenes. Then what should be the general protocol for synthesis of secondary and tertiary amines? A common and sensible approach is to use electrophilesDepartment other than of alkyl Chemistry, halides which give St. relatively Paul's unreactive C. productsM. College with amines. The best examples are acyl halides, aldehydes and ketones in place of alkyl halides. The products of these reactions, the amides and the imines, are in higher oxidation state than the amines and thus they must be reduced to get to the target amines. Thus:

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Lecture note prepared by Kaushik Basu, St. Paul’s C. M. College, Kolkata

The amide reduction method dutifully installs a –CH2– group next to the N-atom, but the imine route using ketones is usually suitable for amines with branched chain. Thus,

The last example is the Borch Reductive Amination reaction, where the intermediate imine is reduced in situ using sodium cyanoborohydride, an acid-stable variant of the more common reducing agent sodium borohydride. This one-pot reaction is considered to be the most important way to make amines in the pharmaceutical industry. The method works because the intermediate imine is less nucleophilic than the amine. Careful control of the pH of the medium is necessary though and ideal pH is ca. 6 to 7. At pH 3 to 4, the reducing agent rapidly reacts with the precursor carbonyl instead of the imine. Instead of the highly toxic NaBH3CN, less hazardous NaBH(OAc)3 can also be used.

Imines are best reduced under acid-catalyzed conditions. Thus the imine route is again suitable for methylation of amines using formaldehyde as the carbonyl component.

The above methods to obtain secondary or tertiary amines can be designated as Reductive Alkylation of primaryDepartment or secondary amines. of ThroughChemistry, Eschweiler- ClarkeSt. Paul's reductive methylationC. M. ,College a primary amine is converted to a secondary or a tertiary amine and a secondary amine is converted to a tertiary amine by the treatment with formaldehyde in formic acid.

The first methylation of the amine begins with imine formation with formaldehyde. The formic acid acts as a source of hydride and reduces the imine via the intermediate formation of iminium ion to a

secondary amine. The driving force is the formation of the gaseous carbon dioxide. Formation of the 8 tertiary amine is similar, but slower due to the difficulties in iminium ion formation. Page

Lecture note prepared by Kaushik Basu, St. Paul’s C. M. College, Kolkata

From the above discussion we may speculate that the reductive alkylation of ammonia, if possible, should lead to a primary amine. There is, indeed, such a reaction referred to as the Leuckart reaction which is analogous to Eschweiler-Clarke methylation. Here the carbonyl compounds are converted to amines by reductive amination on heating with ammonium formate.

In Leuckart reaction ammonium formate first dissociates into formic acid and ammonia. Ammonia then reacts with the carbonyl compound to form an iminium ion under the acidic condition. Formic acid then reduces the intermediate iminium ion to form an amine and carbon dioxide.

It is important to note that both these reactions are carried out under acidic condition and the reducing agent is formic acid. We have already encountered sodium cyanoborohydride, the acid-stable version of the more common reducing agent sodium borohydride. Thus we have the following sequence of reactions:

In the reductive amination step ammonium chloride or ammonium acetate acts as a source of ammonia. The mechanistic details of each step are similar to that of Leuckart Reaction and Eschweiler-Clarke MethylationDepartment while cyanoborohydride of Chemistry, ion acts as a source St. ofPaul's hydride ion C. in placeM. ofCollege formic acid. The reductive alkylation of ammonia via the intermediate formation of primary amide can be used to obtain primary amine also. However, with few exceptions such as the following synthesis of neopentyl amine:

primary amines are not usually made by the reduction of primary amides, i.e. 9 Page

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but by reduction of cyanides:

This method is especially suitable for benzyl amines since aryl cyanides can be made from diazonium salts through Sandmeyer Reaction and for the homologous amines since cyanide ion reacts easily with benzyl halides. Thus,

However, a much better method analogous to the above concept is the reduction of oximes which are more stable intermediates than imines and can be accessed from corresponding carbonyl compounds easily:

For example,

The reduction of oxime cleaves the weak N-O bond as well as the C=N bond is reduced.

Evidently, we cannot obtain primary amines containing t-alkyl groups i.e. t-alkyl-NH2 through the above routes. Recall that to access such amines, we may use the alkylation and concomitant reduction of aliphatic nitro compounds.

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Also recall that the tertiary-butyl amine can be synthesised via Ritter reaction.

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Lecture note prepared by Kaushik Basu, St. Paul’s C. M. College, Kolkata

Identification and distinction between the three classes of amines:

Reaction with nitrous acid

A) Primary amines:

Diazotization with concomitant loss of nitrogen gas (effervescence) leading to a horde of products such as alcohols, amines or olefins. For example, let us consider the reaction of n-butylamine with nitrous acid generated in situ by sodium nitrite and hydrochloric acid:

B) Secondary amines:

Secondary amines react with nitrous acid to form N-nitrosamines which have oil-like appearance and are steam-volatile. This, on Liebermann’s nitroso test responds favourably.

What actually happens?

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It is important to note that secondary amines do not liberate nitrogen gas when treated with nitrous acid but forms yellow oil which is strongly indicative of the presence of such amines; this can be confirmed the colour reaction mentioned above. 11 Page

Lecture note prepared by Kaushik Basu, St. Paul’s C. M. College, Kolkata

C) Tertiary amines:

Upon reacting with nitrous acid, tertiary amines neither liberate any nitrogen gas, nor do they separate any oil. They dissolve in the aqueous reaction medium forming nitrite salts.