Hemiaminal Explained

In organic chemistry, a hemiaminal (also carbinolamine) is a functional group or type of chemical compound that has a hydroxyl group and an amine attached to the same carbon atom: . R can be hydrogen or an alkyl group. Hemiaminals are intermediates in imine formation from an amine and a carbonyl by alkylimino-de-oxo-bisubstitution.^[1] Hemiaminals can be viewed as a blend of aminals and geminal diol. They are a special case of amino alcohols.

Classification according to amine precursor

Hemiaminals form from the reaction of an amine and a ketone or aldehyde. The hemiaminal is sometimes isolable, but often they spontaneously dehydrate to give imines.^[2]

Addition of ammonia

The adducts formed by the addition of ammonia to aldehydes have long been studied.^[3] Compounds containing both a primary amino group and a hydroxyl group bonded to the same carbon atom are rarely stable, as they tend to dehydrate to form imines which polymerise to hexamethylenetetramine. A rare stable example is the adduct of ammonia and hexafluoroacetone, .^[4]

The C-substituted derivatives are obtained by reaction of aldehydes and ammonia:^[5]

3 RCHO + 3 NH3 -> (RCHNH)3 + 3 H2O

Addition of primary amines

N-substituted derivatives are somewhat stable. They are invoked but rarely observed as intermediates in the Mannich reaction. These N,N',N''-trisubstituted hexahydro-1,3,5-triazines arise from the condensation of the amine and formaldehyde as illustrated by the route to 1,3,5-trimethyl-1,3,5-triazacyclohexane:

3 CH2O + 3 H2NMe -> (CH2NMe)3 + 3 H2O

Although adducts generated from primary amines or ammonia are usually unstable, the hemiaminals have been trapped in a cavity.^[6]

Addition of secondary amines: carbinolamines (hemiaminals) and bisaminomethanes

One of the simplest reactions entails condensation of formaldehyde and dimethylamine. This reaction produces first the carbinolamine (a hemiaminal) and bis(dimethylamino)methane :^{[7] [8]}

Me2NH + CH2O -> Me2NCH2OH

Me2NH + Me2NCH2OH -> Me2NCH2NMe2 + H2O

The reaction of formaldehyde with carbazole, which is weakly basic, proceed similarly:^[9]

Again, this carbinol converts readily to the methylene-linked bis(carbazole).

Hemiaminal ethers

Hemiaminal ethers have the following structure: R‴-C(NR'₂)(OR")-R⁗. The glycosylamines are examples of cyclic hemiaminal ethers.

Use in total synthesis

Hemiaminal formation is a key step in an asymmetric total synthesis of saxitoxin:^[10]

In this reaction step the alkene group is first oxidized to an intermediate acyloin by action of osmium(III) chloride, oxone (sacrificial catalyst) and sodium carbonate (base).

See also

• Aminal
• Alkanolamine
• Hemiacetal

Notes and References

1. 10.1021/ed077p1644. Carbinolamines and Geminal Diols in Aqueous Environmental Organic Chemistry. 2000. Urbansky. Edward T.. Journal of Chemical Education. 77. 12. 1644. 2000JChEd..77.1644U.
2. Book: 10.1016/B0-08-044705-8/00206-5 . Functions Incorporating a Chalcogen and a Group 15 Element . Comprehensive Organic Functional Group Transformations . 1995 . Gabbutt . Christopher D. . Hepworth . John D. . 293–349 . 9780080447056 .
3. Justus Liebig "Ueber die Producte der Oxydation des Alkohols" Annalen der Pharmacie 1835, Volume 14, pp 133–167.
4. W. J. Middleton, H. D. Carlson . Hexafluoroacetone imine . Org. Syntheses . 50. 1970. 81–3. 10.15227/orgsyn.050.0081. .
5. Nielsen . Arnold T. . Atkins . Ronald L. . Moore . Donald W. . Scott . Robert . Mallory . Daniel . LaBerge . Jeanne M. . Jeanne LaBerge. 1973 . Structure and Chemistry of the Aldehyde Ammonias. 1-Amino-1-Alkanols, 2,4,6-Trialkyl-1,3,5-Hexahydrotriazines, and N,N-Dialkylidene-1,1-Diaminoalkanes . J. Org. Chem. . 38 . 19 . 3288–3295 . 10.1021/jo00959a010 .
6. 10.1126/science.1143272. Stabilization of Labile Carbonyl Addition Intermediates by a Synthetic Receptor. 2007. Iwasawa. T.. Hooley. R. J.. Rebek. J.. Science. 317. 5837. 493–496. 17656719. 2007Sci...317..493I. 37292853.
7. Book: Aminoalkylierung. 1960. Hellmann Heinrich, Günter Opitz. Weinheim.
8. 10.1021/j100599a008. Thermochemistry of Carbonyl Addition Reactions. II. Enthalpy of Addition of Dimethylamine to Formaldehyde. 1974. Rogers. F. E.. Rapiejko. R. J.. The Journal of Physical Chemistry. 78. 6. 599–603.
9. Carbazol-9-yl-methanol Milata Viktora, Kada Rudolfa, Lokaj J¨¢nb Molbank 2004, M354 open access publication http://www.mdpi.net/molbank/molbank2004/m0354.htm
10. 10.1021/ja071501o. (+)-Saxitoxin: A First and Second Generation Stereoselective Synthesis. 2007. Fleming. James J.. McReynolds. Matthew D.. Du Bois. J.. Journal of the American Chemical Society. 129. 32. 9964–9975. 17658800.