Amine
In
The substituent −NH2 is called an
Compounds with a nitrogen atom attached to a carbonyl group, thus having the structure R−C(=O)−NR′R″, are called amides and have different chemical properties from amines.
Classification of amines
Amines can be classified according to the nature and number of substituents on nitrogen. Aliphatic amines contain only H and alkyl substituents. Aromatic amines have the nitrogen atom connected to an aromatic ring.
Primary (1°) amine | Secondary (2°) amine | Tertiary (3°) amine |
---|---|---|
Amines, alkyl and aryl alike, are organized into three subcategories (see table) based on the number of carbon atoms adjacent to the nitrogen (how many hydrogen atoms of the ammonia molecule are replaced by hydrocarbon groups):[6][7]
- Primary (1°) amines—Primary amines arise when one of three hydrogen atoms in .
- Secondary (2°) amines—Secondary amines have two organic substituents (alkyl, aryl or both) bound to the nitrogen together with one hydrogen. Important representatives include dimethylamine, while an example of an aromatic amine would be diphenylamine.
- Tertiary (3°) amines—In tertiary amines, nitrogen has three organic substituents. Examples include EDTA.
A fourth subcategory is determined by the connectivity of the substituents attached to the nitrogen:
- Cyclic amines—Cyclic amines are either secondary or tertiary amines. Examples of cyclic amines include the 3-membered ring aziridine and the six-membered ring piperidine. N-methylpiperidine and N-phenylpiperidine are examples of cyclic tertiary amines.
It is also possible to have four organic substituents on the nitrogen. These species are not amines but are
Naming conventions
Amines are named in several ways. Typically, the compound is given the prefix "amino-" or the suffix "-amine". The prefix "N-" shows substitution on the nitrogen atom. An organic compound with multiple amino groups is called a
Lower amines are named with the suffix -amine.
Higher amines have the prefix amino as a functional group. IUPAC however does not recommend this convention,[8] but prefers the alkanamine form, e.g. butan-2-amine.
Physical properties
The nitrogen atom features a
3) > secondary ammonium (R
2NH+
2) > tertiary ammonium (R3NH+). Small aliphatic amines display significant solubility in many solvents, whereas those with large substituents are lipophilic. Aromatic amines, such as aniline, have their lone pair electrons conjugated
Spectroscopic identification
Typically the presence of an amine functional group is deduced by a combination of techniques, including mass spectrometry as well as NMR and IR spectroscopies. 1H NMR signals for amines disappear upon treatment of the sample with D2O. In their
Structure
Alkyl amines
Alkyl amines characteristically feature tetrahedral nitrogen centers. C-N-C and C-N-H angles approach the idealized angle of 109°. C-N distances are slightly shorter than C-C distances. The
Amines of the type NHRR' and NRR′R″ are
Aromatic amines
In aromatic amines ("anilines"), nitrogen is often nearly planar owing to conjugation of the lone pair with the aryl substituent. The C-N distance is correspondingly shorter. In aniline, the C-N distance is the same as the C-C distances.[10]
Basicity
Like ammonia, amines are bases.[11] Compared to alkali metal hydroxides, amines are weaker.
Alkylamine[12] or aniline[13] | pKa of protonated amine |
Kb[clarification needed] |
---|---|---|
Methylamine (MeNH2) | 10.62 | 4.17×10−4 |
Dimethylamine (Me2NH) | 10.64 | 4.37×10−4 |
Trimethylamine (Me3N) | 9.76 | 5.75×10−5 |
Ethylamine (EtNH2) | 10.63 | 4.27×10−4 |
Aniline (PhNH2) | 4.62 | 4.17×10−10 |
4-Methoxyaniline (4-MeOC6H4NH2) | 5.36 | 2.29×10−9 |
N,N-Dimethylaniline (PhNMe2) | 5.07 | 1.17×10−9 |
3-Nitroaniline (3-NO2-C6H4NH2) | 2.46 | 2.88×10−12 |
4-Nitroaniline (4-NO2-C6H4NH2) | 1.00 | 1.00×10−13 |
4-Trifluoromethylaniline (CF3C6H4NH2) | 2.75 | 5.62×10−12 |
The basicity of amines depends on:
- The electronic properties of the substituents (alkyl groups enhance the basicity, aryl groups diminish it).
- The degree of solvation of the protonated amine, which includes steric hindranceby the groups on nitrogen.
Electronic effects
Owing to inductive effects, the basicity of an amine might be expected to increase with the number of alkyl groups on the amine. Correlations are complicated owing to the effects of solvation which are opposite the trends for inductive effects. Solvation effects also dominate the basicity of aromatic amines (anilines). For anilines, the lone pair of electrons on nitrogen delocalizes into the ring, resulting in decreased basicity. Substituents on the aromatic ring, and their positions relative to the amino group, also affect basicity as seen in the table.
Solvation effects
Solvation significantly affects the basicity of amines. N-H groups strongly interact with water, especially in ammonium ions. Consequently, the basicity of ammonia is enhanced by 1011 by solvation. The intrinsic basicity of amines, i.e. the situation where solvation is unimportant, has been evaluated in the gas phase. In the gas phase, amines exhibit the basicities predicted from the electron-releasing effects of the organic substituents. Thus tertiary amines are more basic than secondary amines, which are more basic than primary amines, and finally ammonia is least basic. The order of pKb's (basicities in water) does not follow this order. Similarly aniline is more basic than ammonia in the gas phase, but ten thousand times less so in aqueous solution.[14]
In aprotic polar solvents such as DMSO, DMF, and acetonitrile the energy of solvation is not as high as in protic polar solvents like water and methanol. For this reason, the basicity of amines in these aprotic solvents is almost solely governed by the electronic effects.
Synthesis
From alcohols
Industrially significant alkyl amines are prepared from ammonia by alkylation with alcohols:[5]
From alkyl and aryl halides
Unlike the reaction of amines with alcohols the reaction of amines and ammonia with alkyl halides is used for synthesis in the laboratory:
In such reactions, which are more useful for alkyl iodides and bromides, the degree of alkylation is difficult to control such that one obtains mixtures of primary, secondary, and tertiary amines, as well as quaternary ammonium salts.[5]
Selectivity can be improved via the
Aryl halides are much less reactive toward amines and for that reason are more controllable. A popular way to prepare aryl amines is the
From alkenes
Disubstituted alkenes react with HCN in the presence of strong acids to give formamides, which can be decarbonylated. This method, the Ritter reaction, is used industrially to produce tertiary amines such as tert-octylamine.[5]
Hydroamination of alkenes is also widely practiced. The reaction is catalyzed by zeolite-based solid acids.[5]
Reductive routes
Via the process of hydrogenation, unsaturated N-containing functional groups are reduced to amines using hydrogen in the presence of a nickel catalyst. Suitable groups include nitriles, azides, imines including oximes, amides, and nitro. In the case of nitriles, reactions are sensitive to acidic or alkaline conditions, which can cause hydrolysis of the −CN group. LiAlH4 is more commonly employed for the reduction of these same groups on the laboratory scale.
Many amines are produced from aldehydes and ketones via reductive amination, which can either proceed catalytically or stoichiometrically.
Aniline (C6H5NH2) and its derivatives are prepared by reduction of the nitroaromatics. In industry, hydrogen is the preferred reductant, whereas, in the laboratory, tin and iron are often employed.
Specialized methods
Many methods exist for the preparation of amines, many of these methods being rather specialized.
Reaction name | Substrate | Comment |
---|---|---|
Staudinger reduction
|
Organic azide | This reaction also takes place with a reducing agent such as lithium aluminium hydride. |
Schmidt reaction | Carboxylic acid | |
Aza-Baylis–Hillman reaction | Imine | Synthesis of allylic amines |
Birch reduction | Imine | Useful for reactions that trap unstable imine intermediates, such as Grignard reactions with nitriles.[15] |
Hofmann degradation | Amide | This reaction is valid for preparation of primary amines only. Gives good yields of primary amines uncontaminated with other amines. |
Hofmann elimination | Quaternary ammonium salt
|
Upon treatment with strong base |
Leuckart reaction | Ketones and aldehydes | Reductive amination with formic acid and ammonia via an imine intermediate |
Hofmann–Löffler reaction | Haloamine | |
Eschweiler–Clarke reaction | Amine | Reductive amination with formic acid and formaldehyde via an imine intermediate |
Reactions
Alkylation, acylation, and sulfonation, etc.
Aside from their basicity, the dominant reactivity of amines is their nucleophilicity.[16] Most primary amines are good ligands for metal ions to give coordination complexes. Amines are alkylated by alkyl halides. Acyl chlorides and acid anhydrides react with primary and secondary amines to form amides (the "Schotten–Baumann reaction").
Similarly, with sulfonyl chlorides, one obtains sulfonamides. This transformation, known as the Hinsberg reaction, is a chemical test for the presence of amines.
Because amines are basic, they neutralize
Amines undergo sulfamation upon treatment with sulfur trioxide or sources thereof:
Diazotization
Amines reacts with nitrous acid to give diazonium salts. The alkyl diazonium salts are of little importance because they are too unstable. The most important members are derivatives of aromatic amines such as aniline ("phenylamine") (A = aryl or naphthyl):
Anilines and naphthylamines form more stable
Aryldiazoniums couple with electron-rich aromatic compounds such as a phenol to form azo compounds. Such reactions are widely applied to the production of dyes.[18]
Conversion to imines
Reduction of these imines gives secondary amines:
Similarly, secondary amines react with ketones and aldehydes to form enamines:
Overview
An overview of the reactions of amines is given below:
Reaction name | Reaction product | Comment |
---|---|---|
Amine alkylation | Amines | Degree of substitution increases |
Schotten–Baumann reaction | Amide | Reagents: acyl chlorides, acid anhydrides |
Hinsberg reaction | Sulfonamides | Reagents: sulfonyl chlorides
|
Amine–carbonyl condensation
|
Imines
| |
Organic oxidation
|
Nitroso compounds | Reagent: peroxymonosulfuric acid |
Organic oxidation
|
Diazonium salt
|
Reagent: nitrous acid |
Zincke reaction | Zincke aldehyde | Reagent: pyridinium salts, with primary and secondary amines |
Emde degradation | Tertiary amine
|
Reduction of quaternary ammonium cations |
Hofmann–Martius rearrangement | Aryl-substituted anilines | |
von Braun reaction | Organic cyanamide | By cleavage (tertiary amines only) with cyanogen bromide |
Hofmann elimination | Alkene | Proceeds by β-elimination of less hindered carbon |
Cope reaction | Alkene | Similar to Hofmann elimination |
Carbylamine reaction | Isonitrile
|
Primary amines only |
Hoffmann's mustard oil test | Isothiocyanate | Carbon disulfide CS2 and mercury(II) chloride HgCl2 are used. Thiocyanate smells like mustard. |
Biological activity
Amines are ubiquitous in biology. The breakdown of
Amine hormones
Hormones derived from the modification of amino acids are referred to as amine hormones. Typically, the original structure of the amino acid is modified such that a –COOH, or carboxyl, group is removed, whereas the –NH+
3, or amine, group remains. Amine hormones are synthesized from the amino acids tryptophan or tyrosine.[22]
Application of amines
Dyes
Primary aromatic amines are used as a starting material for the manufacture of azo dyes. It reacts with nitrous acid to form diazonium salt, which can undergo coupling reaction to form an azo compound. As azo-compounds are highly coloured, they are widely used in dyeing industries, such as:
- Methyl orange
- Direct brown 138
- Sunset yellowFCF
- Ponceau
Drugs
Most drugs and drug candidates contain amine functional groups:[23]
- Chlorpheniramine is an antihistaminethat helps to relieve allergic disorders due to cold, hay fever, itchy skin, insect bites and stings.
- Chlorpromazine is a tranquilizer that sedates without inducing sleep. It is used to relieve anxiety, excitement, restlessness or even mental disorder.
- Ephedrine and phenylephrine, as amine hydrochlorides, are used as decongestants.
- Amphetamine, methamphetamine, and methcathinone are psychostimulant amines that are listed as controlled substances by the US DEA.
- Thioridazine, an antipsychotic drug, is an amine which is believed to exhibit its antipsychotic effects, in part, due to its effects on other amines.[24]
- Amitriptyline, imipramine, lofepramine and clomipramine are tricyclic antidepressants and tertiary amines.
- tricyclic antidepressantsand secondary amines. (The tricyclics are grouped by the nature of the final amino group on the side chain.)
- Substituted tryptamines and phenethylamines are key basic structures for a large variety of psychedelic drugs.
- Opiate analgesics such as morphine, codeine, and heroin are tertiary amines.
Gas treatment
Aqueous
Epoxy resin curing agents
Amines are often used as epoxy resin curing agents.
Safety
Low molecular weight simple amines, such as ethylamine, are only weakly toxic with LD50 between 100 and 1000 mg/kg. They are skin irritants, especially as some are easily absorbed through the skin.[5] Amines are a broad class of compounds, and more complex members of the class can be extremely bioactive, for example strychnine.
See also
- Acid-base extraction
- Amine value
- Amine gas treating
- Ammine
- Biogenic amine
- Ligand isomerism
- IUPAC)
References
- ^ "amine". The American Heritage Dictionary of the English Language (5th ed.). HarperCollins.
- ^ "Amine definition and meaning". Collins English Dictionary. Archived from the original on 23 February 2015. Retrieved 28 March 2017.
- ^ "amine – definition of amine in English". Oxford Dictionaries. Archived from the original on 23 February 2015. Retrieved 28 March 2017.
- ISBN 0-534-16218-5
- ^ ISBN 978-3527306732.
- ^ ISBN 978-0-07-337562-5. Archived from the original(Book) on 28 June 2018. Retrieved 26 June 2018.
- ^ "3.11 Basic properties of amines". Chemistry LibreTexts. 28 September 2015. Archived from the original on 23 May 2021. Retrieved 23 May 2021.
- ^ Hellwich, K.-H.; Hartshorn, R. M.; Yerin, A.; Damhus, T.; Hutton, A. T. (June 2021). "Brief Guide to the Nomenclature of Organic Chemistry" (PDF). The International Union of Pure and Applied Chemistry (IUPAC). Retrieved 7 March 2024.
- ^ Smith, Brian (March 2019). "Organic Nitrogen Compounds II: Primary Amines". Spectroscopy. Spectroscopy-03-01-2019. 34: 22–25. Retrieved 12 February 2024.
- ISBN 9780470771082.
- .
- PMID 15675863.
- ISBN 978-0-471-72091-1
- .
- ISBN 0-471-60180-2
- ^ A. N. Nesmajanow (1943). "β-Naphthylmercuric chloride". Organic Syntheses; Collected Volumes, vol. 2, p. 432.
- ISBN 3527306730.
- PMID 9512720.
- ISBN 1-57259-153-6.
- S2CID 30690389.
- ISBN 978-1-947172-04-3.
- PMID 21504168.
- ^ American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 2510
- ISBN 3527306730.
- ^ "amine curing agent: Topics by Science.gov". science.gov. Retrieved 1 March 2022.
- ISSN 0369-9420.
- ISBN 3527306730.
Further reading
- "Amines | Introduction to Chemistry". courses.lumenlearning.com. Retrieved 22 July 2021.
- Flick, Ernest W. (1993). Epoxy Resins, Curing Agents, Compounds, and Modifiers: An Industrial Guide. Park Ridge, NJ: Noyes Publications. OCLC 915134542.
External links
- Synthesis of amines
- Factsheet, amines in food Archived 19 February 2018 at the Wayback Machine