Hemiaminal

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: −C(OH)(NR2)−. 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.

Generic hemiaminal

Classification according to amine precursor

Addition of ammonia
Methanolamine, a simple hemiaminal

The adducts formed by the addition of ammonia to aldehydes have long been studied.[2] 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, (CF3)2C(OH)NH2.[3]

The C-substituted derivatives are obtained by reaction of aldehydes and ammonia:[4]

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:

Although adducts generated from primary amines or ammonia are usually unstable, the hemiaminals have been trapped in a cavity.[5]

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 (Me = CH3):[6][7]

The reaction of formaldehyde with carbazole, which is weakly basic, proceed similarly:[8]

reaction of carbazole with formaldehyde to Carbazol-9-yl-methanol

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:[9]

Hemiaminal formation in saxitox in synthesis

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

References
  1. Urbansky, Edward T. (2000). "Carbinolamines and Geminal Diols in Aqueous Environmental Organic Chemistry". Journal of Chemical Education. 77 (12): 1644. Bibcode:2000JChEd..77.1644U. doi:10.1021/ed077p1644.
  2. Justus Liebig "Ueber die Producte der Oxydation des Alkohols" Annalen der Pharmacie 1835, Volume 14, pp 133–167. doi:10.1002/jlac.18350140202
  3. W. J. Middleton, H. D. Carlson (1970). "Hexafluoroacetone imine". Org. Syntheses. 50: 81–3. doi:10.15227/orgsyn.050.0081..
  4. Nielsen, Arnold T.; Atkins, Ronald L.; Moore, Donald W.; Scott, Robert; Mallory, Daniel; LaBerge, Jeanne M. (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. doi:10.1021/jo00959a010.
  5. Iwasawa, T.; Hooley, R. J.; Rebek, J. (2007). "Stabilization of Labile Carbonyl Addition Intermediates by a Synthetic Receptor". Science. 317 (5837): 493–496. Bibcode:2007Sci...317..493I. doi:10.1126/science.1143272. PMID 17656719. S2CID 37292853.
  6. Hellmann Heinrich, Günter Opitz (1960). Aminoalkylierung. Weinheim.{{cite book}}: CS1 maint: location missing publisher (link)
  7. Rogers, F. E.; Rapiejko, R. J. (1974). "Thermochemistry of Carbonyl Addition Reactions. II. Enthalpy of Addition of Dimethylamine to Formaldehyde". The Journal of Physical Chemistry. 78 (6): 599–603. doi:10.1021/j100599a008.
  8. Carbazol-9-yl-methanol Milata Viktora, Kada Rudolfa, Lokaj J¨¢nb Molbank 2004, M354 open access publication Archived 2018-09-26 at the Wayback Machine
  9. Fleming, James J.; McReynolds, Matthew D.; Du Bois, J. (2007). "(+)-Saxitoxin: A First and Second Generation Stereoselective Synthesis". Journal of the American Chemical Society. 129 (32): 9964–9975. doi:10.1021/ja071501o. PMID 17658800.
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