Secondary amines acidity

Dimethyl Sulphate Method for hydroxy compounds and for primary and secondary amines, acid amides, etc. The substance is dissolved or suspended in water, a small excess (above the theoretical) of sodium hydroxide added and then the theoretical quantity of dimethyl sulphate, the mixture being finally shaken without external warming. Methylation is usually rapid, the dimethyl sulphate being converted to methyl hydrogen sulphate... 

Secondary amine acid acceptors can terminate chain growth by reacting with the diadd halide unless amine reactivity is minimized by steric effects. Reactions between a tertiary amine add acceptor and the acid halide or certain solvents must also be avoided. An add chloride and a tertiary amine can react to form a monoamide and an alkyl halide (Equation 13.20). This reaction is known to occur in fair yield at high temperatures and probably takes place to some extent at room temperature [67-69]. In the usual preparative method wherein diacid halide is added to a solution of diamine and a strongly basic acid acceptor, no difficulty is experienced if the polycondensation reaction is rapid. As the polycondensation reaction rate decreases, the potential for interference by side reactions increases. In a polymerization system, this would be a chain terminating reaction. 

Precaution Wear neoprene gloves, safety glasses with side shields incompat. with primary and secondary amines, acids, alkalies, free radical producing initiators Hazardous Decomp. Prods. CO, COj NFPA Health 2, Flammability 1, Reactivity 1... 

Fischer-Hepp rearrangement The nitros-amines of aromatic secondary amines when treated with hydrochloric acid give nuclear substituted nitrosoamines. Among the benzene derivatives, if the para position is free the -NO group displaces the hydrogen atom there in naphthalene derivatives it enters the 1-position ... 

If a primary or secondary amine is heated with glacial acetic acid, the... 

Secondary amines of both the aliphatic and the aromatic series react similarly with nitrous acid, giving nilrosamines ... 

Diasomethane Method. Diazomethane readily methylates phenolic hydroxy-compounds, primary and secondary amines, and carboxylic acids,... 

The Formaldehyde-Formic Acid Method, This method applies to primary and secondary amines, which when boiled with a formalin-formic acid mixture undergo complete methylation to the corresponding tertiary amine. This method has the advantage over the dimethyl sulphate method in that quaternary salts clearly cannot be formed. 

If the molecular weight of the aniline is known, the number of amino groups can be calculated alternatively, if the aniline is known to be a monacidic base, its molecular weight can be calculated. If the molecular weight and the acidity of the aniline are both known, then dearly the method can be used to estimate the amount of aniline in a given sample. The method is general for many primary and secondary amines, aniline being used solely as a typical member of the former class. 

By the hydrolysis of dialkyl cyanamides with dilute sulphuric acid this method gives pure secondary amines. The appropriate dialkyl cyanamide is prepared by treating sodium cyanamide (itself obtained in solution from... 

To 5 ml. of water add 1-2 drops of the secondary amine if it does not dissolve, add a drop or two of concentrated hydrochloric acid. Place 1 ml. of the reagent in a test-tube, add 0 -5-1 ml. of concentrated ammonia solution, followed by 0-5-1 ml. of the above amine solution, A precipitate indicates a secondary amine. A shght turbidity points to the presence of a secondary amine as an impurity. 

Secondary amines upon treatment with nitrous acid yield nitrosamiues, which are stable, neutral yellow liquids (or low melting point solids), for example ... 

Dissolve 1 g. of the secondary amine in 3-5 ml. of dilute hydrochloric acid or of alcohol (in the latter case, add 1 ml. of concentrated hydrochloric acid). Cool to about 5° and add 4-5 ml. of 10 per cent, sodium nitrite solution, and allow to stand for 5 minutes. Add 10 ml. of water, transfer to a small separatory funnel and extract the oil with about 20 ml. of ether. Wash the ethereal extract successively with water, dilute sodium hydroxide solution and water. Remove the ether on a previously warmed water bath no flames should be present in the vicinity. Apply Liebermann s nitroso reaction to the residual oil or solid thus. Place 1 drop or 0 01-0 02 g. of the nitroso compovmd in a dry test-tube, add 0 05 g. of phenol and warm together for 20 seconds cool, and add 1 ml. of concentrated sulphuric acid. An intense green (or greenish-blue) colouration will be developed, which changes to pale red upon pouring into 30-50 ml. of cold water the colour becomes deep blue or green upon adding excess of sodium hydroxide solution. 

Method 1. Treat 2 0 g. of the mixture of amines with 40 ml. of 10 per cent, sodium hydroxide solution and add 4 g. (3 ml.) of benzenesulphonyl chloi de (or 4 g. of p-toluenesulphonyl chloride) in small portions. Warm on a water bath to complete the reaction. Acidify the alkaline solution with dilute hydrochloric acid when the sulphonamides of the primary and secondary amines are precipitated. Filter off the solid and wash it with a little cold water the tertiary amine will be present in the filtrate. To convert any disulphOnamide that may have been formed from the primary amine into the sulphonamide, boil the solid under reflux with 2 0 g. of sodium dissolved in 40 ml. of absolute ethyl alcohol for 30 minutes. Dilute with a little water and distil off the alcohol filter off the precipitate of the sulphonamide of the secondary amine. Acidify the filtrate with dilute hydrochloric acid to precipitate the derivative of the primary amine. Recrystallise the respective derivatives from alcohol or from dilute alcohol, and identify them inter alia by a determination of the m.p. 

Method 2. Place a 3 0 g. sample of the mixture of amines in a flask, add 6g. (4-5 ml.) of benzenesulphonyl chloride (or 6 g. of p-toluenesulphonyl chloride) and 100 ml. of a 5 per cent, solution of sodium hydroxide. Stopper the flask and shake vigorously until the odour of the acid chloride has disappeared open the flask occasionally to release the pressure developed by the heat of the reaction. AUow the mixture to cool, and dissolve any insoluble material in 60-75 ml. of ether. If a solid insoluble in both the aqueous and ether layer appears at this point (it is probably the sparingly soluble salt of a primary amine, e.g., a long chain compound of the type CjH5(CH2) NHj), add 25 ml. of water and shake if it does not dissolve, filter it off. Separate the ether and aqueous layers. The ether layer will contain the unchanged tertiary amine and the sulphonamide of the secondary amine. Acidify the alkaline aqueous layer with dilute hydrochloric acid, filter off the sulphonamide of the primary amine, and recrystaUise it from dilute alcohol. Extract the ether layer with sufficient 5 per cent, hydrochloric acid to remove all the tertiary amine present. Evaporate the ether to obtain the sulphonamide of the secondary amine recrystaUise it from alcohol or dilute alcohol. FinaUy, render the hydrochloric acid extract alkaline by the addition of dilute sodium hydroxide solution, and isolate the tertiary amine. 

Derivatives with 3-nitrophthalic anhydride. 3-Nitrophthalic anhydride reacts with primary and secondary amines to yield nitro-phthalamic acids it does not react with tertiary amines. The phthalamic acid derived from a primary amine undergoes dehydration when heated to 145° to give a neutral A -substituted 3-nitrophthalimide. The phthalamic acid from a secondary amine is stable to heat and is, of course, soluble in alkali. The reagent therefore provides a method for distinguishing and separating a mixture of primary and secondary amines. 

Formyl derivatives. Formic acid condenses with primary and secondary amines to yield formyl derivatives ... 

Knoevenagel reaction. The condensation of an aldehyde with an active methylene compound (usually malonic acid or its derivatives) in the presence of a base is generally called the Knoevenagel reaction. Knoevenagel found that condensations between aldehydes and malonic acid are effectively catalysed by ammonia and by primary and secondary amines in alcoholic solution of the organic amines piperidine was regarded as the best catalyst. 

In the above reaction one molecular proportion of sodium ethoxide is employed this is Michael s original method for conducting the reaction, which is reversible and particularly so under these conditions, and in certain circumstances may lead to apparently abnormal results. With smaller amounts of sodium alkoxide (1/5 mol or so the so-called catal3rtic method) or in the presence of secondary amines, the equilibrium is usually more on the side of the adduct, and good yields of adducts are frequently obtained. An example of the Michael addition of the latter type is to be found in the formation of ethyl propane-1 1 3 3 tetracarboxylate (II) from formaldehyde and ethyl malonate in the presence of diethylamine. Ethyl methylene-malonate (I) is formed intermediately by the simple Knoevenagel reaction and this Is followed by the Michael addition. Acid hydrolysis of (II) gives glutaric acid (III). 

This acid chloride is much less reactive than acetyl chloride and indeed it may be employed to benzoylate a primary or secondary amine in the presence of a dilute... 

Benzenesulphonyl chloride test. Proceed as in the benzoyl chloride test, but use 15-20 ml. of 5 per cent, sodium hydroxide solution. Examine the product when the odour of the sulphonyl chloride has disappeared. (If no reaction has occurred, the substance is probably a tertiary amine.) If a precipitate appears in the alkaline solution, dilute with about 10 ml. of water and shake if the precipitate does not dissolve, a secondary amine is indicated. If the solution is clear, acidify it cautioiosly to Congo red with dilute hydrochloric acid a precipitate is indicative of a primary amine. 

There also exists an acidregioselective condensation of the aldol type, namely the Mannich reaction (B. Reichert, 1959 H. Hellmann, 1960 see also p. 291f.). The condensation of secondary amines with aldehydes yields Immonium salts, which react with ketones to give 3-amino ketones (=Mannich bases). Ketones with two enolizable CHj-groupings may form 1,5-diamino-3-pentanones, but monosubstitution products can always be obtained in high yield. Unsymmetrical ketones react preferentially at the most highly substituted carbon atom. Sterical hindrance can reverse this regioselectivity. Thermal elimination of amines leads to the a,)3-unsaturated ketone. Another efficient pathway to vinyl ketones starts with the addition of terminal alkynes to immonium salts. On mercury(ll) catalyzed hydration the product is converted to the Mannich base (H. Smith, 1964). 

Primary and secondary amines also react with epoxides (or in situ produced episulfides )r aziridines)to /J-hydroxyamines (or /J-mercaptoamines or 1,2-diamines). The Michael type iddition of amines to activated C—C double bonds is also a useful synthetic reaction. Rnally unines react readily with. carbonyl compounds to form imines and enamines and with carbo-tylic acid chlorides or esters to give amides which can be reduced to amines with LiAlH (p. Ilf.). All these reactions are often applied in synthesis to produce polycyclic alkaloids with itrogen bridgeheads (J.W. Huffman, 1967) G. Stork, 1963 S.S. Klioze, 1975). 

A special problem arises in the preparation of secondary amines. These compounds are highly nucleophilic, and alkylation of an amine with alkyl halides cannot be expected to stop at any specifle stage. Secondary amides, however, can be monoalkylated and lydrolyzed or be reduced to secondary amines (p. 11 If.). In the elegant synthesis of phenyl- phrine an intermediate -hydroxy isocyanate (from a hydrazide and nitrous acid) cyclizes to pve an oxazolidinone which is monomethylated. Treatment with strong acid cleaves the cyclic irethan. 

A) Sn2 substitution at the allylic alcohol with hydrobromic acid followed by reaction with the requisite secondary amine, or... 

Hydroxylysine (328) was synthesized by chemoselective reaction of (Z)-4-acet-oxy-2-butenyl methyl carbonate (325) with two different nucleophiles first with At,(9-Boc-protected hydroxylamine (326) under neutral conditions and then with methyl (diphenylmethyleneamino)acetate (327) in the presence of BSA[202]. The primary allylic amine 331 is prepared by the highly selective monoallylation of 4,4 -dimethoxybenzhydrylamine (329). Deprotection of the allylated secondary amine 330 with 80% formic acid affords the primary ally-lamine 331. The reaction was applied to the total synthesis of gabaculine 332(203]. 

Some recent general reviews deal with the mechanism of N-nitrosation in aqueous solution (345), the nitrosation of secondary amines (346). the effect of solvent acidity On diazotization (347) and the reactivity of diazonium salts (1691). Therefore, a complete rationalization of the reactivity of amino azaaromatics would be timelv. 

Nitriles react with ammonia, or primary or secondary amines in the presence of an acid catalyst to give amidines (Scheme 26) (75, 77, 81). The catalysts used are hydrochloric acid and aluminium chloride. The amidines are anthelmintics for animals such as sheep, goats, cattle, horses, and Swine. 

Nitrosation (Section 22 15) The reaction of a substance usu ally an amine with nitrous acid Pnmary amines yield dia zonium 10ns secondary amines yield N nitroso amines Tertiary aromatic amines undergo nitrosation of their aro matic ring... 

Although acetyl chloride is a convenient reagent for deterrnination of hydroxyl groups, spectroscopic methods have largely replaced this appHcation in organic chemical analysis. Acetyl chloride does form derivatives of phenols, uncompHcated by the presence of strong acid catalysts, however, and it finds some use in acetylating primary and secondary amines. 

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