Ammonia1

NH3

[7664-41-7]  · H3N  · Ammonia  · (MW 17.03)

(weak base;2 essential nonaqueous solvent medium for dissolving metal reactions;3 precursor of organic nitrogen compounds including amines,4 unsubstituted amides,5 heterocycles1,6)

Physical Data: mp -78 °C; bp -33.3 °C/760 mmHg; d liq. NH3 0.682 g cm-3 (-33.3 °C/760 mmHg).

Solubility: very sol water (47.8% w/w, 0 °C), methanol, ethanol; also sol chloroform, ether.

Form Supplied in: although gaseous at room temperature, anhydrous NH3 is usually supplied as the liquified form in stainless steel cylinders which are sometimes fitted with an eductor tube to permit convenient and rapid extraction of liquid NH3 when the cyclinder is inverted or tipped on its side. NH3 is also readily available as aqueous solutions (ammonium hydroxide) in various concentrations. Drying: commercial anhydrous NH3 can be used as supplied in many applications though in some cases drying is required to ensure optimum yield. Gaseous NH3 can be dried by passing through a column of NaOH pellets, whereas liquid NH3 can be dried using sodium metal (sufficient to obtain a persistent deep-blue coloration) or CaH2 followed by distillation under nitrogen directly into the reaction vessel.

Handling, Storage, and Precautions: since NH3 is highly corrosive, cylinders must be equipped with the appropriate stainless steel valves and fittings. As a consequence of its comparatively high enthalpy of vaporization (23.5 kJ mol-1), reactions involving liquid ammonia can be carried out on laboratory scale without the need for external cooling since an insulating layer of ice quickly builds up around the outside of the reaction vessel.

NH3 is highly toxic; inhalation of the vapor can cause edema of the respiratory tract, spasm of the glottis, and asphyxia. All reactions involving anhydrous ammonia must be conducted in a well-ventilated fume hood.

.

As a consequence of the lone pair of electrons on the nitrogen, ammonia is both a weak base (Kb 1.8 × 10-5) and a nucleophile, two properties which account for most of its reagent chemistry.2 Ammonia reacts readily and reversibly with mineral and organic acids to form salts (eq 1) which, being stable solids, are often used as convenient sources of ammonia. Since ammonia is an extremely weak acid (pKa estimated to be ~38),7 the amide anion is a very strong base.

Ammonia in Dissolving Metal Reactions.

In addition to dissolving a wide range of organic compounds and inorganic salts, anhydrous liquid NH3 can act as a solvent for the Group 1 and 2 metals, producing deep-blue colored solutions which conduct electricity and are strongly reducing. The physical and chemical properties of such solutions are usually attributed to solvated electrons.3,8 In the presence of a catalyst such as anhydrous Fe(NO3)3, solutions of sodium and potassium in liquid NH3 are conveniently converted into the amide salts (M+NH2-), which are very strong bases.9

Solutions of Li, Na, and K metals in liquid NH3, usually in the presence of a proton source like ethanol, have been extensively used for the partial reduction of a variety of benzene derivatives and polyfused aromatic compounds (the Birch reduction);2 typically, benzene gives 1,4-cyclohexadiene (eq 2) whereas naphthalene is reduced to the tetrahydro derivative. o-Methoxybenzoic acid (also its salts and esters) can be converted to 2-alkylcyclohexenones (eq 3).10 Similar reaction conditions have been utilized for the ring opening of cyclopropanes,11 the transformation of conjugated enones to the saturated carbonyl compounds12 or their 2-substituted derivatives,13 the stereospecific reduction of disubstituted alkynes to (E)-alkenes,14 the hydrodehalogenation of gem-dihalides,15 and the reductive cleavage of polysulfides to thiols.16

Alkylation of Ammonia.

Direct reactions between ammonia and alkyl halides are complex and generally produce mixtures of the salts of the primary, secondary, and tertiary amines, and also quarternary salts (eqs 4-7). The final composition of the product mixture depends on the relative initial concentrations of the reactants, the nature of the reaction solvent, and the steric requirements of the alkyl groups. The reactions generally exhibit the characteristics of SN2 type displacements (reaction rate with respect to the alkyl group: primary > secondary > tertiary) and the ease of halogen displacement follows the expected order I > Br > Cl > F.4b Reactions carried out in liquid ammonia tend to give mixtures of primary and secondary amines, whereas in methanolic ammonia more complex mixtures of the primary, secondary, and tertiary amines are obtained.17 Separation of the various amine products by distillation is usually easier for higher alkyl substituents, e.g. n-octyl.18

With dihaloalkanes, intramolecular cyclization will occur to form five- to seven-membered heterocyclic compounds as appropriate, though even in favorable cases, over reaction can occur (eq 8).19 Tribromoalkanes have also been used to synthesize novel azabicyclic systems (eq 9),20 and l-azaadamantane (eq 10).21

Amination of Aromatic and Heteroaromatic Compounds.

Although amination of simple aryl halides to yield anilines by ipso substitution of the halo group is more usually carried out using Potassium Amide in liquid NH3, NH3 itself can also be used but requires elevated temperatures and pressure, and a copper catalyst.22 Thus, for example, aniline is obtained from chlorobenzene (200 °C, Cu cat.),23 3,4-dimethylaniline from 4-bromo-o-xylene (195 °C, Cu/CuCl),24 and p-trifluoromethylaniline from p-chlorotrifluoromethylbenzene (200 °C, CuCl/KF).25

The amination reaction proceeds more smoothly if the benzene ring is activated by strongly electron-withdrawing groups, particularly NO2, in the o- and p-positions. The ease of halide displacement follows the sequence F > Br > Cl > I.22b Nitro groups have also been displaced from 2,3-dinitrotoluene.26

Naphthol derivatives can be transformed to the corresponding amines by treatment with aqueous ammonia in the presence of sulfite or bisulfite ion at elevated temperatures (the Bucherer reaction) (eq 11);27 the analogous transformation with phenols is known, but is less common.28

Heteroaromatic compounds, particularly pyridines and diazines, are more susceptible to amination with NH3 than arenes. Although the amination reactions generally proceed under milder conditions, they may also be catalyzed by Cu salts. Typical examples include the Cu-catalyzed conversion of 3-bromopyridine to 3-aminopyridine, and 2-chloro-3-aminopyridine to 2,3-diaminopyridine,29 the aminolysis of fluoro-30 and chloropyrazines31 on treatment with aqueous NH3 at room temperature and 180 °C respectively, the displacement of the methoxy group in 4-methoxypyrimidone to give cytosine on treatment with methanolic ammonia at 100 °C (eq 12),32 and the selective transformation of 2,6-dichloropurine to the corresponding 6-amino-2-chloro derivative under similar conditions (eq 13).33 Treatment of solutions of 3-halo-2-alkylisothiazolium salts in acetonitrile with excess ammonia yields exclusively the N-monosubstituted 3-isothiazoles via a ring opening/recyclization process (eq 14).34 Irradiation of solutions of 6-phenyl- and 6-t-butyl-4-halopyrimidines in liq NH3 with UV light affords the corresponding 4-amino derivatives.35

Highly p-electron deficient nitroaza heterocycles (including pyridines, diazines, and their respective benzo compounds) react with Potassium Permanganate in liq NH3 to give amino compounds via an SNH mechanism involving the initial formation of a s-adduct with NH3 which is subsequently oxidized by the permanganate.36 The reactions can be highly regioselective and give high product yields (>80%) (eq 15).37 For less p-electron deficient compounds, the combination KNH2/liq NH3/KMnO4 has been used.38

a-Amino Acids.

Ammonia reacts readily with a-halo carboxylic acids to yield the corresponding a-amino acids (eq 16). The reactions are conveniently carried out using a large excess of ammonia with either ammonium chloride39 or formaldehyde40 present to suppress further alkylation. The displacement normally proceeds with inversion of configuration41 unless the adjacent b-position is substituted.42

Ring-Opening of Epoxides and Aziridines.

Epoxides, possessing a relatively high degree of ring strain, readily open on treatment with ammonia to give 1,2-amino alcohols, usually with a high degree of regio- and stereoselectivity.43 Consistent with an SN2 mechanism, nucleophilic attack by the ammonia occurs at the sterically least hindered carbon center of the epoxide, e.g. with propene,44 butene,45 and styrene45,46 oxides (eq 17). The ring opening proceeds in a trans fashion with concomitant inversion of configuration, e.g. trans-2-butene oxides give erythro-amino alcohols, whereas the cis compounds afford the diastereoisomeric threo-amino alcohols (eq 18).47 Aminolysis of cyclopentene48 and cyclohexene49 oxides produces the corresponding trans-amino alcohols; the cyclohexane derivative is also obtained from the reaction of trans-chlorohydrin with aqueous ammonia at room temperature.48 Substitution at the 3-position directs the incoming ammonia to the more distal carbon center (eq 19).50 With epoxides derived from six-membered ring compounds which have rigid geometries, the amino and hydroxy groups in the resulting product are normally trans diaxially related, an important consideration in the stereoselective syntheses of amino sugars.43,51

Ring opening of aziridines by anhydrous NH3 in the presence of ammonium chloride proceeds smoothly at 100 °C to give 1,2-diamines.52 The regio- and stereochemical preferences of this reaction have been shown to be similar to those observed for epoxides.47

a-Amino Nitriles.

These key intermediates in the Strecker synthesis of amino acids (see below) can be prepared from the reaction of cyanohydrins with ammonia.53 a-Amino nitriles (yields 80-95 %) can be conveniently prepared from a-silyloxy nitriles on treatment with ammonia in methanol (eq 20).54

Amidines.

Formamidine Acetate, a relatively nonhygroscopic salt, is conveniently obtained in high yield from the reaction of Triethyl Orthoformate with ammonia in acetic acid at 115 °C (eq 21). The corresponding acetamidine salt is prepared in a similar fashion using NH4Cl in ammonia.55

Primary Amides.

Nucleophilic substitution by ammonia at the carbonyl carbon of a carboxylic acid or a related derivative provides a general synthetic route to unsubstituted or primary amides (eq 22).5 The order of reactivity is carboxylic acids < esters < anhydrides < acyl chlorides.

Since direct reaction between a carboxylic acid and NH3 requires vigorous reaction conditions (reaction temperatures 170-200 °C), excess NH3, and continuous removal of the water formed, this method is only suitable for amides derived from thermally stable acids; at higher temperatures, nitrile formation competes. Nonetheless, the primary amides from a series aliphatic carboxylic acids (C2-C18) have been prepared by this approach.56,57 Under similar reaction conditions, cyclic imides (favorable for ring sizes 5 and 6) can be obtained from diacids and NH3.58

Although esters react cleanly with ammonia to give the corresponding amides, the reported conditions to effect the transformation are still reasonably vigorous, e.g. excess conc aq NH3/NH4Cl at 100 °C,59 or liq NH3 at 165-180 °C.60 Ethyl cyanoacetate affords cyanoacetamide on shaking with aqueous NH3.61 As an alternative method, esters are transformed to primary amides under mild conditions (CH2Cl2/T < 40 °C) using Me2AlNH2 (2 equiv), generated in situ from AlMe3 and NH3.62

The ammonolysis of acyl chlorides has been used extensively as a standard laboratory procedure for the preparation of primary amides, the reactions are rapid and exothermic and usually carried out in solvent.5,60,63 To ensure completion of reaction, a minimum of a twofold excess of ammonia is required since it reacts with the HCl liberated. Instead of ammonia, ammonium acetate in acetone can be used with acyl chlorides.64

Carboxylic acid anhydrides readily undergo ammonolysis to give the corresponding primary amide.5 With cyclic anhydrides, cyclic imides are formed, e.g. phthalic anhydride gives phthalimide.58

Treatment of mixed anhydrides, generated in situ from carboxylic acids and Ethyl Chloroformate, with anhydrous ammonia provides primary amides under mild conditions;5,65 product yields are claimed to be superior to those obtained using acyl chlorides.66

Reactions conditions for the ammonolyses of substituted esters and acyl chlorides can usually be adapted to be compatible with a range of functionality including unsaturation,67 halo,68,69 hydroxyl,70 amino,71 and acetal groups.72 For example, a-halocarboximides can be obtained from the corresponding acid chlorides68 or esters69 with conc aq NH3 by maintaining the reaction temperature below 0 °C.

Aromatic or allylic aldehydes can be converted into primary amides by reaction with NH3 using either Nickel(II) Peroxide in dry Et2O at -20 °C,73 or Sodium Cyanide and Manganese Dioxide in isopropanol at 0 °C.74 Amination of aliphatic and aryl aldehydes has also been accomplished using N-Bromosuccinimide with AIBN as an initiator in the presence of NH3; radical substitution of the aldehydic hydrogen by Br generates an acyl bromide which reacts rapidly with the NH3 present.75

Primary amides are obtained from the thermal,76a photochemical,76b or metal ion (e.g. Ag+) catalyzed77 rearrangement of a-diazo ketones in the presence of ammonia (Wolff rearrangement). In cases where the required diazo ketone can be generated in situ from an acyl chloride and Diazomethane, the overall transformation is an homologation (the Arndt-Eistert synthesis) (eq 23).77

The Ugi Reaction.

Ammonia, usually in the form of an ammonium salt of a carboxylic acid, reacts with a mixture of isocyanides and aldehydes to give bis-amides in moderate yield (~50%) (the Ugi reaction) (eq 24).78 The scope of the reaction is considerably more limited with ammonia than with amines.

Addition of Ammonia to Alkenes and Alkynes.

Since it is intrinsically nucleophilic, NH3 does not form adducts readily with simple alkenes. Under high temperature (200 °C) and pressures (800-1000 atm), and in the presence of Na metal, ethylene, propene, isobutene, and cyclohexene react with NH3 to give the corresponding amines in low yield (15-30%).79 Similarly, 2-phenylethylamine is obtained from styrene in 8% yield.80 NH3 does, however, undergo nucleophilic addition to PdII and PtII complexes derived from 1,5-dienes; subsequent reduction of the adducts with Sodium Borohydride releases the amines, e.g. 2-aminohexane (93%) and cyclooctylamine (57%) are obtained from 1,5-hexadiene and 1,5-cycloocatdiene, respectively.81

Simple alkenes undergo aminosulfenylation on treatment in turn with Dimethyl(methylthio)sulfonium Tetrafluoroborate followed by ammonia (eq 25).82

Alkenes with electron withdrawing substituents (carbonyl, nitrile, alkoxycarbonyl) are susceptible to Michael addition to form, at least initially, the b-amino adducts. With systems unsubstituted at the b-position, multiple addition usually occurs affording the di- and triadducts even with a large excess of ammonia (eq 26). Thus, the diadduct is the major product from the addition of NH3 to acrylonitrile at 30 °C even with a significant excess of NH3. When the reaction is carried out with a large excess of NH3 (>threefold) at 110 °C for short reaction times, the monoadduct is the major component of the reaction mixture.83 Ethyl acrylate reacts readily with NH3 to give the corresponding di- and triadducts which are separable by distillation.84

Substitution at the b-position of a,b-unsaturated systems inhibits multiple addition. Thus crotonic acid,85 ethyl crotonate,86 and mesityl oxide87 all form the corresponding b-amino compounds. 1-Nitropropene and butene also form monoadducts with ammonia which tend to be unstable.88 Sorbic acid undergoes double addition of NH3 to give 3,5-diaminohexanoic acid.89

As with alkenes, reactions between simple alkynes and NH3 generally take place under forcing reaction conditions, producing complex product mixtures containing 1,2-diamines, piperidines, etc.90 Conjugated dialkynes react with NH3 in the presence of CuCl catalyst to give pyrroles (eq 27).91

Addition of Ammonia to Heterocumulenes.

NH3 adds across the carbon-carbon double bond of ketenes to give primary amides, usually in good yield (cf. the Wolff rearrangement mentioned above) (eq 28).92

With isocyanates and isothiocyanates, the addition of NH3 takes place specifically across the carbon-nitrogen double bond, producing ureas93 and thioureas, respectively (eq 29).94

Amidines.

Alkyl and aryl nitriles react with ammonia in the presence of ammonium salts to give amidine salts, usually in yields of the order of 80% (eq 30).95 The reaction between nitriles and MeAl(Cl)NH2, generated in situ from AlMe3 and NH4Cl, provides an alternative general synthetic route to amidines.96 Dinitriles of suitable chain length give cyclic imidines on treatment with NH3 in methanol at 100 °C (eq 31).97

Addition of Ammonia to Carbonyl Compounds.

Nucleophilic addition of NH3 to an aldehyde or ketone affords initially a hemiaminal which subsequently dehydrates to an imine (eq 32). Imines which are not readily isolable except those derived from perfluoroalkyl98 or diaryl ketones99 usually react further. Condensations of ammonia with (a) formaldehyde yield the polycyclic adduct hexamethylenetetramine (eq 33),100 (b) n-alkanals and arylacetaldehydes form the trimeric hexahydrotriazines (eq 34),101 and (c) aromatic aldehydes give hydrobenzaminidines (eq 35).102

Reductive Amination.

Catalytic hydrogenation (Ni, Pt, Rh) of mixtures of aldehydes or ketones (usually in ethanol) and NH3 affords primary amines, presumably by hydrogenation of the intermediate imine (eq 36).103 Aliphatic carbonyl compounds with at least five carbon atoms (lower molecular weight compounds are too reactive) or aromatic aldehydes are found to be most suitable. Since the primary amines formed initially are potential substrates for reaction, further alkylation may occur giving secondary and tertiary amines.

Treatment of aromatic aldehydes or aliphatic ketones, which are not soluble in water, with either NH3/Formic Acid or Ammonium Formate yields the corresponding primary amines (Leuckart reaction).104

Mannich Reaction.

The product mixtures from condensation reactions between ketones which possess at least one a-hydrogen atom, Formaldehyde, and NH3 are generally more complex than those obtained from the corresponding reactions in which the NH3 is replaced by a secondary amine such as dimethylamine.105 Thus acetophenone affords a mixture of the di- and triadducts rather than the expected b-amino ketone (Mannich base) (eq 37).106 Mannich reactions involving dibenzyl ketones with formaldehyde and NH3 in a relative molar ratio of 1:5:2 respectively give adamantane-like diaza ketones in good yields (eq 38).107

Strecker Synthesis of a-Amino Acids.

Aldehydes react with Hydrogen Cyanide in the presence of ammonia to yield an a-amino nitrile which on subsequent hydrolysis is converted to an a-amino acid (eq 39).108 a-Substituted a-amino acids can be prepared from ketones.109 a-Silyloxy nitriles offer an alternative route to the required intermediate amino nitriles (see eq 20).54

Willgerodt Reaction.

Heating mixtures of alkyl aryl ketones with ammonium polysulfide (or sulfur and dry NH3) affords primary amides or the ammonium salts of the carboxylic acid (eq 40).110 Side reactions become more pronounced as the chain length increases.

With acyclic and cyclic aliphatic ketones (2 equiv), sulfur, and NH3, D3-thiazoline derivatives can be obtained. In addition, treatment of methyl ketones, which can only be thiolated on the methyl group (e.g. acetophenone and pinacolone), with a large excess of sulfur (~eightfold) affords D3-imidazoline-5-thiones.111

Nitriles.

Gas phase co-pyrolyses of (a) aliphatic mono- or dicarboxylic acids over silica gel at 500 °C112 or (b) primary alcohols over a 15% Cu/alumina catalyst at 300 °C113 with NH3 afford mono- or dinitriles as appropriate in good yield.

Benzaldehydes are converted to the corresponding benzonitriles on treatment with NH3 in the presence of either Iodine114 or Lead(IV) Acetate.115

Miscellaneous Reactions Involving Ammonia.

Liq NH3 is found to be a convenient medium and a mild base for the deprotection of FMOC-protected amino acids (eq 41).116 Removal of Na-benzyloxycarbonyl protecting groups for sulfur-containing peptides by Pd-catalyzed hydrogenolysis proceeds smoothly in liq NH3 because poisoning of the catalyst is substantially diminished.117

a-Acetyl-b-keto esters are readily deacylated on treatment with gaseous NH3 in dry Et2O (eq 42).118

NH3 is a participating solvent in ozonolysis reactions; ozonolyses of indene and indole in the presence of NH3 afford isoquinoline and quinazoline, respectively.119 Diamines are obtained in 50-60% yield from cyclic alkenes by a sequence involving ozonolysis in methanol and partial reduction of the resulting reaction mixture followed by catalytic hydrogenation over Rh or Raney Nickel at 200-400 psi/50 °C.120

The Borane-Ammonia complex, prepared in situ from NH3 and diborane or available commercially, reduces carbonyl compounds rapidly; aldehydes are selectively reduced in the presence of aliphatic and aromatic acyclic ketones.121 Moreover, the NH3-BH3 complex reacts faster than NaBH4 with hindered ketones.

Ammonia in the Synthesis of Nitrogen-Containing Heterocycles.

Ammonia has been used extensively for the introduction of nitrogen atoms into heterocyclic ring systems. Space does not permit an adequate discussion of the various methods. For further details, see the general overview by Jeyaraman1 and specialist monographs and reviews for systems such as pyridines,6a,b pyrroles,6c,d and diazines.122


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Kevin J. McCullough

Heriot-Watt University, Edinburgh, UK



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