Gabriel synthesis phthalimide

Better yields are generally obtained by the Gabriel phthalimide synthesis (Problem 11, p. 744) the a-halo esters are used instead of a-halo acids (Why ). A further modification, the phthalimidomalonic ester method, is a combined malonic ester-Gabriel synthesis. 

Gabriel phthalimide synthesis, 12, 10 Gattermann-Koch synthesis of an aldehyde, 12, 80 Gelatine, 12, 4... 

We have already encountered an important synthesis of amino acids in the sequence of Figure 22.18—a Hell-Volhard-Zelinskii reaction followed by amination of the a-halo acid. There is no multiple substitution of the ammonia because the electron-withdrawing effect of the carboxylic acid makes the amine less nucleophilic. Also, as soon as it is formed, the acid converts to the zwitterionic form. An alternative process uses the Gabriel phthalimide synthesis (Figure 22.19). 

Primaty amines may be prepared from alkyl halides using phthalimide. This is called the Gabriel amine synthesis. 

Another alternative for preparing a primary amine from an alkyl halide is the Gabriel amine synthesis, which uses a phthalimide alkylation. An imide (—CONHCO—) is similar to a /3-keto ester in that the acidic N-H hydrogen is flanked by two carbonyl groups. Thus, imides are deprotonated by such bases as KOH, and the resultant anions are readily alkylated in a reaction similar to the acetoacetic ester synthesis (Section 22.7). Basic hydrolysis of the N-alkylated imide then yields a primary amine product. The imide hydrolysis step is analogous to the hydrolysis of an amide (Section 21.7). 

Gabriel amine synthesis (Section 24.6) A method for preparing an amine by SN2 reaction of an alkyl halide with potassium phthalimide. followed by hydrolysis. 

Phosphine(s), chirality of, 314 Phosphite, DNA synthesis and, 1115 oxidation of, 1116 Phospholipid, 1066-1067 classification of, 1066 Phosphopantetheine, coenzyme A from. 817 structure of, 1127 Phosphoramidite, DNA synthesis and, 1115 Phosphoranc, 720 Phosphoric acid, pKa of, 51 Phosphoric acid anhydride, 1127 Phosphorus, hybridization of, 20 Phosphorus oxychloride, alcohol dehydration with. 620-622 Phosphorus tribromide, reaction with alcohols. 344. 618 Photochemical reaction, 1181 Photolithography, 505-506 resists for, 505-506 Photon, 419 energy- of. 420 Photosynthesis, 973-974 Phthalic acid, structure of, 753 Phthalimide, Gabriel amine synthesis and, 929... 

The starting reagents in Gabriel amine synthesis, N-alkylphthalimides, were obtained under the action of microwave irradiation in a solid-liquid PTC system. The reactions were conducted with high yield (50-90%) simply by mixing phthalimide... 

Gabriel s synthesis org chem A synthesis of primary amines by the hydrolysis of n-alkylphthallmldes the latter are obtained from potassium phthalimide and alkyl halides. ga-bre-alz, sin-tha-sas ... 

A variant of Gabriel amine synthesis where hydrazine is used to release the amine from the corresponding phthalimide ... 

Phase-transfer catalysed N-alkylation of diphenylphosphinic amide (I) is totally unsuitable in the case of easily hydrolysable organic halides, especially those containing additional functional groups (i.e. carbonyl or carboalkoxyl) which decompose readily in strongly alkaline medium. To circumvent the difficulty connected with simultaneous mono- and dialkylation of (I) under anhydrous conditions, N-(t-butyloxycarbonyl) diethyl phosphoroamidate (X), a doubly-protected ammonia derivative, was devised as a useful and superior substitute of phthalimide in the Gabriel-type synthesis of amines. 

Under acidic conditions the equilibrium for the hydrolysis of an amide is driven toward the products by the protonation of the ammonia or amine that is formed. Under basic conditions the equilibrium is driven toward the products by the formation of the carboxylate anion, which is at the bottom of the reactivity scale. The pH of the final solution may need to be adjusted, depending on which product is to be isolated. If the carboxylic acid is desired, the final solution must be acidic, whereas isolation of the amine requires that the solution be basic. Several examples are shown in the following equations. Also, note that the last step of the Gabriel amine synthesis, the hydrolysis of the phthalimide (see Section 10.6 and Figure 10.5 on page 365), is an amide... 

In 1887, Siegmund Gabriel (at the University of Berlin) developed the Gabriel amine synthesis for making primary amines without danger of over-alkylation. He used the phthalimide anion as a protected form of ammonia that cannot alkylate more than once. Phthalimide has one acidic N—H proton (pKa 8.3) that is abstracted by potassium hydroxide to give the phthalimide anion. 

Potassium phthalimide, CgH CO NK Reacts with alkyl halides to yield N-alkyl-phthalimides, which are hydrolyzed by aqueous sodium hydroxide to yield amines (Gabriel amine synthesis Section 24.6). 

In Gabriel s synthesis of primary amines, potassium phthalimide is reacted with an alkyl halide and the resulting A-alkylphthalimide is hydrolysed to release the amine and phthalic acid (Scheme 5.12). This route is also used in the synthesis of amino acids. 

An alternative to the azide synthesis is the Gabriel amine synthesis, which uses a phthalimide alkylation for preparing a primary amine from an alkyl halide. Imides (-CONHCO-) are similar to ethyl acetoacetate in that... 

Problem 24.8 Write the mechanism of the last step in the Gabriel amine synthesis, the base-promoted hydrolysis of a phthalimide to yield an amine plus phthalate ion. 

Sato, M., Ebine, S., Akabori, S. Condensation of halobenzenes and haloferrocenes with phthalimide in the presence of copper(l) oxide a simplified Gabriel reaction. Synthesis 1981,472 73. 

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