04/12/2016
NAME: Aliyu Isa Mohammed
DEPARTMENT: Microbiology
ID Nō: 15/08/06/278
COURSE: Chem221 (Organic chemistry IIA)
DATE: 01/12/2016
The chemistry and postulation of Gabriel's and clammensen's reactions
The Gabriel synthesis is a chemical reaction that transforms primary alkyl halides into primary amines. Traditionally, the reaction uses potassium phthalimide.[1][2][3] The reaction is named after the German chemist Siegmund Gabriel.[4]
The Gabriel reaction has been generalized to include the alkylation of sulfonamides and imides, followed by deprotection, to obtain amines (see Alternative Gabriel reagents).[5][6]
The alkylation of ammonia is often an unselective and inefficient route to amines. In the Gabriel method, phthalimide anion is employed as a surrogate of H2N−.
Traditional Gabriel synthesis
Edit
In this method, the sodium or potassium salt of phthalimide is N-alkylated with a primary alkyl halide to give the corresponding N-alkylphthalimide.[7][8][9] The reaction fails with most secondary alkyl halides:
500px-Gabriel_Synthesis_Scheme.png
Upon workup by acidic hydrolysis the primary amine is liberated as the amine salt.[10] Alternatively the workup may be via the Ing–Manske procedure, involving reaction with aqueous or ethanolic hydrazine at reflux. This method produces a precipitate of phthalhydrazide along with the primary amine. The first technique often produces bad yields or side products; separation of phthalhydrazide can be unpleasant. For these reasons, other methods for liberating the amine from the phthalimide exist.[11] Even with the use of the hydrazinolysis method, the Gabriel method suffers from relatively harsh conditions.
600px-Gabriel_synthesis_mechanism.png
Mechanism of the Gabriel synthesis
Alternative Gabriel reagents
Many alternative reagents have been developed to complement the use of phthalimides. Most such reagents, e.g. the sodium salt of saccharin, and di-tert-butyl-iminodicarboxylate. These reagents are electronically similar to the phthalimide salts, consisting of imido nucleophiles.. In terms of their advantages, these reagents hydrolyze more readily, extend the reactivity to secondary alkyl halides, and allow the production of secondary amines.[6]
alkyl halides
Alkylation of Phthalimide (Gabriel synthesis of Primary Alkyl Amines)
gabriel.gif
Reaction type: Nucleophilic substitution then Nucleophilic Acyl Substitution
Summary
The advantage of this method is that over alkylation is avoided (see previous page)
Reaction of phthalimide with KOH removes the N-H proton giving an imide ion, a good nucleophile.
Nucleophilic substitution by the imide ion on the alkyl halide generates an intermediate, N-alkyl phthalimide.
Hydrolysis or hydrazinolysis liberates a primary alkyl amine.
Aryl amines cannot be prepared via this method since aryl halides do not undergo simple nucleophilic substitution.
MECHANISM OF THE GABRIEL SYNTHESIS
Step 1:
An acid/base reaction. Deprotonation of the imide N-H proton by the base, hydroxide. This proton is more acidic than a simple amine due to the resonance stabilisation by the two adjacent C=O groups. This generates a strong nucleophile, the -ve N.
gabrielmech.gif
Step 2:
The N nucleophile attacks the electrophilic C of the alkyl halide displacing the bromide and creating the new C-N bond. This product can be compared to an N-alkyl amide.
Clemmensen Reduction
Clemme2.gif
The Clemmensen Reduction allows the deoxygenation of aldehydes or ketones, to produce the corresponding hydrocarbon.
The substrate must be stable to strong acid. The Clemmensen Reduction is complementary to the Wolff-Kishner Reduction, which is run under strongly basic conditions. Acid-labile molecules should be reduced by the Wolff-Kishner protocol.
Mechanism of the Clemmensen Reduction
The reduction takes place at the surface of the zinc catalyst. In this reaction, alcohols are not postulated as intermediates, because subjection of the corresponding alcohols to these same reaction conditions does not lead to alkanes. The following proposal employs the intermediacy of zinc carbenoids to rationalize the mechanism of the Clemmensen Reduction:
Clemme1.gif
Clemme2.gif
The Clemmensen Reduction allows the deoxygenation of aldehydes or ketones, to produce the corresponding hydrocarbon.
The substrate must be stable to strong acid. The Clemmensen Reduction is complementary to the Wolff-Kishner Reduction, which is run under strongly basic conditions. Acid-labile molecules should be reduced by the Wolff-Kishner protocol.
Mechanism of the Clemmensen Reduction
The reduction takes place at the surface of the zinc catalyst. In this reaction, alcohols are not postulated as intermediates, because subjection of the corresponding alcohols to these same reaction conditions does not lead to alkanes. The following proposal employs the intermediacy of zinc carbenoids to rationalize the mechanism of the Clemmensen Reduction:
Clemme1.gif
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