Chemistry
Gabriel Synthesis
Gabriel Synthesis is a method used to prepare primary amines from potassium phthalimide and alkyl halides. The reaction involves the formation of an intermediate, which is then hydrolyzed to yield the desired primary amine. This method is widely used in organic synthesis.
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5 Key excerpts on "Gabriel Synthesis"
- David R. Klein(Author)
- 2017(Publication Date)
- Wiley(Publisher)
CHAPTER 22 917 22.12. (a) We begin by identifying an alkyl halide that can serve as a precursor: In the Gabriel Synthesis, phthalimide is the starting material, and three steps are required. In the first step, phthalimide is deprotonated by hydroxide to give potassium phthalimide, which can serve as a nucleophile and attack the alkyl halide above in an SN2 process. Subsequent treatment with hydrazine (or aqueous acid) releases the desired amine: (b) We begin by identifying a halide that can serve as a precursor: In the Gabriel Synthesis, phthalimide is the starting material, and three steps are required. In the first step, phthalimide is deprotonated by hydroxide to give potassium phthalimide, which can serve as a nucleophile and attack the halide above in an SN2 process. Subsequent treatment with hydrazine (or aqueous acid) releases the desired amine: N O O H 1) KOH 3) H 2 NNH 2 2) NH 2 Br (c) We begin by identifying an alkyl halide that can serve as a precursor: In the Gabriel Synthesis, phthalimide is the starting material, and three steps are required. In the first step, phthalimide is deprotonated by hydroxide to give potassium phthalimide, which can serve as a nucleophile and attack the alkyl halide above in an SN2 process. Subsequent treatment with hydrazine (or aqueous acid) releases the desired amine: (d) We begin by identifying an alkyl halide that can serve as a precursor: In the Gabriel Synthesis, phthalimide is the starting material, and three steps are required. In the first step, phthalimide is deprotonated by hydroxide to give potassium phthalimide, which can serve as a nucleophile and attack the alkyl halide above in an SN2 process. Subsequent treatment with hydrazine (or aqueous acid) releases the desired amine: 918 CHAPTER 22 22.13. The problem statement dictates that a Gabriel Synthesis be employed, so we begin by identifying a suitable alkyl halide that can be converted into compound 2 via a Gabriel Synthesis.
eBook - PDF- David R. Klein(Author)
- 2021(Publication Date)
- Wiley(Publisher)
One such alternative employs hydrazine to release the amine and involves two successive nucleophilic acyl substitution reactions. N O O R N R H H N N O O H H H 2 N NH 2 + SKILLBUILDER 22.2 PREPARING A PRIMARY AMINE VIA THE GABRIEL REACTION Amphetamine is a stimulant (stronger than caffeine) that increases alertness and decreases appetite. It was used extensively during World War II to prevent combat fatigue. NH 2 Amphetamine Using a Gabriel Synthesis, show how amphetamine can be prepared. SOLUTION First identify an alkyl halide that can serve as a precursor in the preparation of amphet- amine. To draw this precursor, simply replace the amino group with a halide: NH 2 Can be made from Br In the Gabriel Synthesis, the nitrogen atom comes from phthalimide, which serves as the starting material. The process requires three steps: (1) deprotonation to form potassium phthalimide, (2) nucleophilic attack with an alkyl halide, and (3) releasing the amine via hydrolysis or via treat- ment with hydrazine. Draw the reagents for all three steps of the Gabriel Synthesis: LEARN the skill STEP 1 Identify an appropriate alkyl halide to use. 22.6 Preparation of Amines via Reductive Amination 1069 N O O H NH 2 Br 1) KOH 2) 3) H 2 NNH 2 Note: Planning a Gabriel Synthesis requires that you identify the alkyl halide to use in the second step of the process. The first and third steps remain the same regardless of the identity of the desired product. 22.12 Using a Gabriel Synthesis, show how you would make each of the following compounds: (a) NH 2 (b) NH 2 (c) NH 2 (d) NH 2 22.13 Fluorescent compounds emit light when excited, and some fluorescent compounds have been used for the detection, or sensing, of small molecules, metals, and changes in pH, among other things. Dapoxylsulfonic acid (DSA) is a fluorescent molecule that responds differently depending on the polarity of its environment, and is thus a unique sensing molecule.
eBook - PDFConcerning Amines
Their Properties, Preparation and Reactions
- David Ginsburg, Robert Robinson(Authors)
- 2016(Publication Date)
- Pergamon(Publisher)
Thus for phthalimide we may write several resonance forms leading to charge delocalization. :NH r ο After a proton is lost we have the anion which is also capable of resonance stabilization. ^ o Phthalimide is sufficiently acidic to form a potassium salt by treatment with concentrated potassium hydroxide solution. Its Ka = 5x 10^. The potassium salt is the reagent used in the Gabriel Synthesis. The phthalimide anion is a good nucleophile. When treated with various halogen containing compounds, it is alkylated in a manner quite similar to that observed in the 3 2 CONCERNING AMINES alkylation of ammonia and of amines even though phthahmide is by no means an amine. |T : N — R + κ+χ-Potassium phthalimide There are several methods for hydrolysing the substituted phthalimide which is formed. It may be boiled with potassium hydroxide solution and this liberates the free primary amine: N -R aq. KOH Heat +RNH2 Alternatively it may be heated with hydrazine to give phthal-hydrazide and the free amine: O Phthalhydrazide The Gabriel Synthesis has been used for the preparation of simple amines as well as amines containing other functional groups. j] :N:ld-+CljCH2C02C,H3 Ethyl chloroacetate I N -C H j C O , C ^ , Heat PROPERTIES, PREPARATION AND REACTIONS 33 HCl ^^:::;X^coNHCH2CO- κ+ Í ^ C O ^ H + CrH3NCHjC02H Phthalic acid Glycine hydrochloride K* + (CHJ)J C=CHCH3CH^BR ll N -C H I C H I C H = C ( C H , ) ^ NH^NH^^ IJ^ J¡¡ + (CH3 )2C = CHCHjCH2NH2 1 -Amino-4-methyl-3-pentene ^^jj^^^ + BrCHjCHjCH^Br ^i-CHjCHjCHjBr n -(C4H ,)2NH HCl -CH2CH2CH2N(C ^H5 )2
eBook - PDFOrganic Chemistry
A Mechanistic Approach
- Penny Chaloner(Author)
- 2014(Publication Date)
- CRC Press(Publisher)
An alternative process uses the Gabriel phthalimide synthesis (Figure 22.19). CH 3 CH 2 COOH (1) P/Br 2 (2) H 2 O Br NH 3 (XS) NH 2 N + H 3 H 3 C H 3 C COOH H 3 C COOH COO – FIGURE 22.18 Synthesis.of.amino.acids. N – K + O O Br N O O COOEt COOEt 1) EtO – 2) RX N O O COOEt COOEt R H 3 O + , Δ H 3 N + COO – R + COOH COOH COOEt COOEt FIGURE 22.19 Gabriel.synthesis.of.amino.acids. Chapter 22 – Amines, Alkaloids, Amino Acids, Peptides, and Nucleic Acids 1065 Ph N H O N H N H N HO O Ot-Bu O O 22.24 We have previously met the Strecker synthesis of amino acids (Figure 22.20, Section 14.3.4); like the two previous methods, this normally produces racemic amino acids. However, if the reaction is catalyzed by various additives such as the Jacobsen catalyst, 22.24, aliphatic α-aminonitriles have been isolated in 80 %–90 % enantiomer excess. Another fairly direct method for the synthesis of chiral amino acids involves the synthesis of a dehydroamino acid, 22.25, which is then hydrogenated in the presence of a chiral rhodium complex. The dehydroamino acid is prepared via an azlactone, with the full mechanism shown in Figure 22.21. The azlactone is then hydrolyzed to the dehydroamino acid. The dehydroamino acid derivative is readily reduced with a standard palladium catalyst, but the product is then race- mic. If the catalyst used is [Rh(COD)(DIPAMP)][BF 4 ], then the reaction proceeds with up to 99 % enantiomer excess (DIPAMP, 22.26). This is the basis of the Monsanto process for the production of the anti-Parkinson’s drug, l-DOPA, 22.27 , and William Knowles received the Nobel Prize for this work in 2001. P P Ph Ph OMe MeO 22.26, R, R-DIPAMP HO HO COOH NH 2 22.27, L-DOPA RCHO + NaCN + NH 3 R CN NH 2 NH 3 HO – , H 2 O R COOH NH 2 R H NH – CN FIGURE 22.20 Strecker.synthesis.of.amino.acids.
eBook - PDFQuaternary Ammonium Salts
Their Use in Phase-Transfer Catalysis
- R. Alan Jones(Author)
- 2000(Publication Date)
- Academic Press(Publisher)
The system is cooled to room temperature and the organic phase is separated. The aqueous phase is extracted with CHCI, (2 x SO ml) and the combined organic solutions are w:ashed with H,O (2 x 100 ml), dried (Na2S0,). and evaporated. The products are purified by chromatography from Kieselgel. In a useful variant of the Gabriel Synthesis of primary amines, diphenylphosphi- namides have been N-alkylated under phase-transfer catalytic conditions (Table 5.26). The alkylation is carried out either directly using primary or secondary bromoalkanes 15 1, 521, or with alkyl inethanesulglionates, produced irz sitif from methanesulphonyl chloride and the appropriate alcohol 1531. Mono- and dialkylation of diphcnylphosphinarnidc is only accorriplished in high y icld ti ndcr 1 iquid : 1 iq uid 1 w 0-ph ase con di t.i o 11 s w i 1 h reac 1.i v e pi m ary bro ti1 o al k an es ; seco n dary bro ti1 oal k an e s require the more vigorous so1id:liqiiici conditions. However, t.he more acidic phosphinanilides can be alkylated by both primary and secondary bromoalkanes in a 1icluid:liquid two-phasc syslcrri 1491. 5.2.24 Synthesis of N-alkylphosphinamides MethodA: The bromoalkane (20 mmol) in PhH is added dropwise over 1.5 h with stimng to Ph,PONH, (4.34 g, 20 mmol), TBA-HSO, (0.34 g, 1 mmol), aqueous NaOH (50%, 50 ml) and PhH (50 ml). The stirred mixture is refluxed for 1.5 h and then cooled to room temperature and diluted with PhH (SO ml). H,O (50 ml) is added and the organic phase is separated. The aqueous phase is extracted with PhH (25 ml) and the organic solutions arc thcn washcd with H,O until neutral? dricd (MgSO,), and cvaporatcd to yicld thc N-alkylated derivative. Mctliod H: The hromoalhane ( 12 r r m o l ) in PhH (2s nil) is added dropwise over a period of I h with stirring to a re.fluxing mixture of the Ph,PONH, (2. I7 g, I0 rnrnol), powdered NaOl I ( I .6 g), K , W I (6.9 g), and T B h I ISO., (0.34 g, I mmol) in PhI I (50 ml). Thc
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