Gabriel Phthalimide Synthesis, Mechanism

Gabriel Phthalimide Synthesis, Mechanism - Reaction with FAQs

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Gabriel phthalimide synthesis

The Gabriel synthesis or Gabriel phthalimide synthesis is named after the German chemist Siegmund Gabriel. Gabriel phthalimide synthesis is a reaction that involves conversion of primary alkyl halides into primary amines using alkyl halides. Conventionally, the Gabriel synthesis uses potassium phthalimide.

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Gabriel phthalimide synthesis
Gabriel phthalimide reaction
Gabriel synthesis mechanism

The Gabriel phthalimide synthesis or Gabriel synthesis has applications in the alkylation of sulfonamides and imides, followed by their deprotection, to obtain amines. The alkylation of ammonia is frequently an extensive and inefficient route to amines. In the Gabriel phthalimide synthesis, phthalimide anion is recruited as a proxy of H₂N⁻.

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Gabriel phthalimide reaction

The main objective of Gabriel phthalimide synthesis is to form primary amine (RNH₂). Gabriel synthesis involves reaction of potassium hydroxide with the phthalimide which forms a good nucleophile in the form of an imide ion. The imide ion attacks alkyl halide via nucleophilic substitution reaction and leads to the formation of an intermediate named as N-alkyl phthalimide. Phthalimide then undergoes hydrolysis which yields a primary alkyl amine. However, aryl amines cannot be prepared through Gabriel synthesis because aryl halides do not undergo simple nucleophilic substitution. Gabriel synthesis has an advantage of eluding the possibility of over alkylation.

Before discussing the mechanism, we could write the overall Gabriel phthalimide reaction as:

the overall Gabriel phthalimide reaction as

Gabriel synthesis mechanism

As we discussed above, Gabriel phthalimide reaction is used for the preparation of primary amines and Gabriel phthalimide reaction is a nucleophilic substitution reaction. Now, we need to understand how this reaction proceeds and how different groups interact with each other to produce primary amines as endgame. The reaction initiates with conversion of phthalimide into potassium phthalimide by addition of alkali base KOH or NaOH. Removal of protons from the nitrogen of phthalimide takes place; this is called deprotonation of nitrogen. In some books this step is skipped.

Gabriel synthesis mechanism

Gabriel phthalimide synthesis then proceeds with potassium phthalimide. The nitrogen of potassium phthalimide gains a negative charge due to deprotonation. This negatively charged nitrogen can now act as a nucleophile and react with alkyl halide via bimolecular nucleophilic substitution reaction or S_N2 reaction.

The nucleophilic nitrogen

The nucleophilic nitrogen of Gabriel phthalimide attacks the electrophilic carbon of alkyl halide. The potassium ion from KOH combines with halogen of alkyl halide and forms KX. The alkyl group of alkyl halide attaches to nucleophilic nitrogen which results in the formation of N-alkyl phthalimide (structure given below).

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The nucleophilic nitrogen

Figure.1. Structure of N-alkyl phthalimide

At this stage of Gabriel phthalimide reaction, there are a couple of variations for generating amines. Generally, hydrazine (NH₂NH₂) is used via the Ing–Manske procedure which produces a precipitate of phthalhydrazide along with the primary amine. Processes like acidic hydrolysis or basic hydrolysis can sometimes be done. Gabriel synthesis involving acidic hydrolysis liberates amine salt from the primary amine. We will discuss how reaction proceeds with addition of hydrazine. Hydrazine is a nucleophile which on adding to carbonyl carbon gives nucleophilic acyl substitution with N-alkyl phthalimide.

Structure of N-alkyl phthalimide

The nitrogen of phthalimide then participates in deprotonation of the protonated hydrazine.

The nitrogen of phthalimide

The nitrogen of hydrazine is deprotonated by nitrogen of phthalimide which leads to the formation of an uncharged species.

The nitrogen of hydrazine

The unreacted NH₂ group of hydrazine undergoes nucleophilic acyl substitution and attacks the carbonyl group liberating amine. Both species generated in this step of Gabriel phthalimide synthesis are charged which need to be taken care of.

The unreacted NH2

The final step of Gabriel phthalimide reaction involves neutralization of charge which results in formation of primary amine RNH₂. This step marks the end of Gabriel phthalimide synthesis.

Alternate methods of Gabriel synthesis

Gabriel phthalimide synthesis using hydrazine often produces low yields or side products. Consecutively, it is not easy to separate phthalhydrazide. This is the main problem which leads to the formulation of other methods to liberate amines from phthalimide. Alternative reagents like the sodium salt of saccharin and di-tert-butyl-iminodicarboxylate are used in place of hydrazine.

Such reagents are electronically similar to phthalimide salts and consist of imido nucleophile. Since Gabriel synthesis is ineffective for secondary alkyl halides, these reagents ensure reactivity of secondary alkyl halides too. These reagents hydrolyze more readily and allow the production of secondary amines. Another common alternative includes acid hydrolysis and base hydrolysis of phthalimide.

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Gabriel phthalimide synthesis involving acid hydrolysis

Gabriel synthesis initiates with H₃O⁺ ion which is made by addition of any acid in aqueous solution. The hydronium ion protonates one of carbon of the carbonyl groups of phthalimide and addition of water takes place which in turn leads to the cleaving of N-alkyl phthalimide. Another molecule of nucleophilic water then attacks the other carbon of carbonyl carbon which develops charge on the molecules. This extra charge forces RNH₂ to detach from carbonyl carbons. The end of Gabriel synthesis is marked by substitution of RNH₂ by OH from the N-alkyl phthalimide which results in formation of an amine.

Gabriel phthalimide synthesis involving basic hydrolysis

Gabriel phthalimide reaction initiates with an attack of OH^- on one of the carbonyl carbon. Nucleophilic OH ion attacks carbon of carbonyl group by nucleophilic substitution reaction. This results in cleaving of N-alkyl phthalimide. During this process the oxygen atom of the carbonyl group gains a negative charge. Another molecule of OH ion attacks the second carbonyl group. This process of charge transfer between nucleophile and electrophile to gain stability and neutralize molecules forces RNH₂ to detach from carbonyl carbon. The nitrogen is replaced by O^- ions. This marks the end of nucleophilic substitution reaction and hence end of Gabriel phthalimide synthesis.

Gabriel phthalimide synthesis

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Frequently Asked Questions (FAQs)

1. Gabriel phthalimide reaction is used for the preparation of which compound?

Gabriel phthalimide synthesis is used for preparation of primary amines

2. Explain Gabriel phthalimide synthesis.

Gabriel synthesis is used for the preparation of primary amines.

The Gabriel synthesis or Gabriel phthalimide synthesis is named after the German chemist Siegmund Gabriel. Gabriel phthalimide synthesis is a chemical reaction that converts primary alkyl halides into primary amines using alkyl halides. Conventionally, the Gabriel synthesis uses potassium phthalimide

Named after	Sigmund Gabriel
Reaction type	Substitution reaction

The main objective of Gabriel phthalimide synthesis is to form primary amine (RNH2). Gabriel synthesis involves reaction of potassium hydroxide with the phthalimide which forms an imide ion which is a good nucleophile. Nucleophilic substitution takes place from the imide ion on the alkyl halide. This leads to the formation of an intermediate named as N-alkyl phthalimide. Phthalimide then undergoes hydrolysis which yields a primary alkyl amine. However, aryl halides do not undergo simple nucleophilic substitution and thus aryl amines cannot be prepared through Gabriel synthesis. Gabriel synthesis has an advantage of eluding the possibility of over alkylation.

3. The method by which aniline cannot be prepared is _.

The method by which aniline cannot be prepared is Gabriel phthalimide synthesis. – Aniline is produced by degradation of benzamide with bromine in alkaline solution. This reaction is called Hoffmann bromamide degradation.

4. N ethyl phthalimide on hydrolysis gives _.

N ethyl phthalimide on hydrolysis gives ethyl amine. N-alkyl phthalimide on hydrolysis gives primary amines via nucleophilic substitution reaction mechanism.

5. Methylamine can be prepared by _.

Methylamine can be prepared by Hoffmann bromamide reaction which involves reaction of ammonia with methanol in the presence of an aluminosilicate catalyst.

6. Can Gabriel synthesis be used to prepare aromatic amines?

No, Gabriel synthesis is not typically used to prepare aromatic amines. It is primarily used for aliphatic primary amines. Aromatic amines are usually prepared by other methods such as reduction of nitro compounds or nucleophilic aromatic substitution.

7. Can Gabriel synthesis be used to prepare amino acids?

Yes, Gabriel synthesis can be used to prepare α-amino acids. This is done by using α-halo acids or their esters as the alkyl halide component. After the synthesis, the carboxylic acid group remains intact, resulting in an amino acid product.

8. Why are polar aprotic solvents like DMF preferred in Gabriel synthesis?

Polar aprotic solvents like DMF are preferred because they can dissolve both the ionic potassium phthalimide and the organic alkyl halide. These solvents do not have acidic hydrogens, which prevents them from interfering with the nucleophilicity of the phthalimide anion. They also promote SN2 reactions by not solvating the nucleophile excessively.

9. What are the limitations of Gabriel synthesis?

Some limitations of Gabriel synthesis include: 1) It works best with primary alkyl halides, 2) The reaction can be slow, often requiring heating, 3) It involves a two-step process, which can reduce overall yield, 4) It's not suitable for large-scale industrial production due to the use of phthalimide, which is relatively expensive.

10. How does the nucleophilicity of phthalimide compare to that of ammonia?

The phthalimide anion is less nucleophilic than ammonia. However, it is more selective, reacting preferentially with primary alkyl halides. This selectivity, combined with its role as a protecting group, makes phthalimide more useful than ammonia for synthesizing primary amines exclusively.

11. Can Gabriel synthesis be used in the preparation of unnatural amino acids?

Yes, Gabriel synthesis can be used to prepare unnatural amino acids. By using appropriately substituted α-halo acids or their esters as the alkyl halide component, various side chains can be introduced. This method is particularly useful for creating amino acids with non-standard side chains.

12. How does the yield of Gabriel synthesis compare to other methods of primary amine synthesis?

Gabriel synthesis often provides good to excellent yields of primary amines, typically in the range of 70-90%. This is generally higher than direct amination methods, which can suffer from poor selectivity and over-alkylation. However, the two-step nature of Gabriel synthesis can sometimes lead to lower overall yields compared to some one-step methods.

13. Why is Gabriel synthesis considered a "protected" synthesis route?

Gabriel synthesis is considered a "protected" route because the phthalimide group acts as a protecting group for the amine. It prevents over-alkylation and formation of secondary or tertiary amines. The phthalimide group is stable during the alkylation step and can be easily removed later to reveal the primary amine.

14. Can Gabriel synthesis be performed under microwave conditions?

Yes, Gabriel synthesis can be performed under microwave conditions. Microwave heating can significantly reduce reaction times from hours to minutes. It provides more uniform heating and can improve yields. However, careful control of reaction parameters is necessary to prevent decomposition or side reactions.

15. Can Gabriel synthesis be used to prepare diamines?

Yes, Gabriel synthesis can be used to prepare diamines. This is typically done by using a dihalide (or ditosylate/dimesylate) as the alkylating agent. Both halide groups can react with phthalimide, and subsequent hydrolysis yields a diamine. This method is particularly useful for preparing symmetrical diamines.

16. What is Gabriel phthalimide synthesis?

Gabriel phthalimide synthesis is a method for preparing primary amines from alkyl halides. It involves reacting potassium phthalimide with an alkyl halide, followed by hydrolysis to yield the primary amine. This method is particularly useful for synthesizing primary amines without producing secondary or tertiary amines as byproducts.

17. Why is Gabriel synthesis preferred over direct amination?

Gabriel synthesis is preferred over direct amination because it selectively produces primary amines. Direct amination often leads to a mixture of primary, secondary, and tertiary amines, which can be difficult to separate. Gabriel synthesis avoids this problem by using phthalimide as a protecting group.

18. What types of alkyl halides work best in Gabriel synthesis?

Gabriel synthesis works best with primary alkyl halides. Secondary alkyl halides react more slowly and may undergo elimination reactions. Tertiary alkyl halides generally do not work well in this synthesis due to steric hindrance and their tendency to undergo elimination reactions.

19. How does phthalimide act as a protecting group in Gabriel synthesis?

Phthalimide acts as a protecting group by forming a stable N-alkylphthalimide intermediate. This intermediate prevents further alkylation, ensuring that only primary amines are formed. The phthalimide group is then easily removed by hydrolysis to reveal the primary amine.

20. What is the role of potassium in potassium phthalimide?

Potassium in potassium phthalimide serves as a counterion, making the phthalimide more nucleophilic. The potassium ion increases the solubility of phthalimide in polar aprotic solvents like DMF, which are commonly used in this reaction. It also enhances the reactivity of the phthalimide anion towards alkyl halides.

21. What conditions are typically used for the hydrolysis step in Gabriel synthesis?

The hydrolysis step in Gabriel synthesis typically uses strong basic conditions, such as aqueous sodium hydroxide or potassium hydroxide. This is often followed by acidification to isolate the free amine. Alternatively, hydrazine can be used for a milder cleavage of the phthalimide group.

22. How does the basicity of the product amine compare to the phthalimide starting material?

The product primary amine is significantly more basic than the phthalimide starting material. Phthalimide is a weak acid with a pKa around 8-9, while primary amines typically have pKa values around 10-11. This difference in basicity is crucial for the final isolation of the amine product.

23. What side products might form during Gabriel synthesis and how can they be minimized?

Possible side products include elimination products (alkenes) from E2 reactions, especially with secondary or tertiary alkyl halides. Unreacted starting materials may also remain. To minimize side products, use primary alkyl halides, control temperature, and ensure anhydrous conditions to prevent hydrolysis of the alkyl halide.

24. What is the significance of using DMF as a solvent in Gabriel synthesis?

DMF (Dimethylformamide) is an excellent solvent for Gabriel synthesis because: 1) It's polar aprotic, promoting SN2 reactions, 2) It can dissolve both ionic and organic compounds, 3) It has a high boiling point, allowing for heated reactions, 4) It doesn't have acidic hydrogens that could interfere with the reaction.

25. Can Gabriel synthesis be used in solid-phase synthesis?

Yes, Gabriel synthesis can be adapted for solid-phase synthesis. In this approach, the phthalimide group is typically attached to a solid support (resin). The alkyl halide then reacts with the immobilized phthalimide. After washing away excess reagents, the product can be cleaved from the resin, often simultaneously hydrolyzing the phthalimide group. This method is useful in combinatorial chemistry and peptide synthesis.

26. What is the mechanism of the first step in Gabriel synthesis?

The first step in Gabriel synthesis involves an SN2 reaction. The nucleophilic nitrogen of the phthalimide anion attacks the carbon bearing the halide in the alkyl halide. This results in the formation of an N-alkylphthalimide intermediate and the displacement of the halide ion.

27. How does the reactivity of different halides (Cl, Br, I) compare in Gabriel synthesis?

The reactivity of halides in Gabriel synthesis follows the general trend for SN2 reactions: I > Br > Cl > F. Iodides are most reactive due to iodine's weaker bond with carbon and its better leaving group ability. Fluorides are rarely used due to the strong C-F bond.

28. Can Gabriel synthesis be used with alkyl tosylates or mesylates instead of halides?

Yes, Gabriel synthesis can be performed with alkyl tosylates or mesylates instead of halides. These sulfonates are excellent leaving groups and often react even faster than halides in SN2 reactions. This can be useful when the corresponding alkyl halide is not readily available or stable.

29. How does temperature affect the rate of Gabriel synthesis?

Increasing the temperature generally increases the rate of Gabriel synthesis. Higher temperatures provide more energy for molecules to overcome the activation energy barrier. However, very high temperatures can lead to side reactions or decomposition of reactants, so optimal temperature depends on the specific substrates.

30. How does the stereochemistry of the alkyl halide affect the product in Gabriel synthesis?

Gabriel synthesis proceeds via an SN2 mechanism, which results in inversion of stereochemistry at the carbon center where substitution occurs. If the alkyl halide has a chiral center at the reactive site, the product will have the opposite configuration at that center.

31. Can Gabriel synthesis be used to prepare secondary amines?

Gabriel synthesis is not directly used to prepare secondary amines. However, the primary amine product from Gabriel synthesis can be further reacted to form secondary amines through various methods such as reductive amination or alkylation.

32. How does the pKa of phthalimide compare to that of other common nitrogen-containing compounds?

Phthalimide has a pKa of about 8-9, making it more acidic than most amines (pKa ~10-11) but less acidic than amides (pKa ~15-20). This intermediate acidity is crucial for its role in Gabriel synthesis, allowing it to form a stable anion while still being basic enough to act as a nucleophile.

33. How does the electron-withdrawing nature of the phthalimide group affect the reactivity of the nitrogen?

The electron-withdrawing nature of the phthalimide group reduces the nucleophilicity of the nitrogen compared to a free amine. This decreased nucleophilicity is actually beneficial in Gabriel synthesis as it prevents over-alkylation and makes the reaction more selective for primary amine formation.

34. What is the role of heat in the alkylation step of Gabriel synthesis?

Heat serves several purposes in the alkylation step: 1) It increases the rate of reaction by providing energy to overcome the activation barrier, 2) It enhances the solubility of reactants, 3) It can help drive off any residual water, maintaining anhydrous conditions. However, excessive heat can promote side reactions, so temperature control is crucial.

35. How does the basicity of the phthalimide anion compare to that of the corresponding amine product?

The phthalimide anion is less basic than the corresponding amine product. This is due to the resonance stabilization of the negative charge in the phthalimide anion across two carbonyl groups. The lower basicity of the phthalimide anion contributes to its selectivity in alkylation reactions.

36. How does the presence of water affect Gabriel synthesis?

Water can negatively affect Gabriel synthesis. In the alkylation step, water can hydrolyze the alkyl halide, reducing yield. It can also promote elimination reactions. In the hydrolysis step, controlled amounts of water are necessary, but excess can lead to incomplete reactions or difficulties in product isolation.

37. What is the importance of the carbonyl groups in the phthalimide structure for Gabriel synthesis?

The carbonyl groups in phthalimide are crucial for Gabriel synthesis because: 1) They make the N-H bond more acidic, facilitating anion formation, 2) They provide resonance stabilization to the phthalimide anion, 3) They withdraw electron density from the nitrogen, preventing over-alkylation, 4) They activate the C-N bonds for cleavage during the hydrolysis step.

38. How does the reactivity of alkyl chlorides, bromides, and iodides compare in Gabriel synthesis?

The reactivity order in Gabriel synthesis is typically: alkyl iodides > alkyl bromides > alkyl chlorides. This follows the general trend of leaving group ability in SN2 reactions. Iodides react fastest due to the weaker C-I bond and iodide's superior leaving group ability. Chlorides react slowest and may require longer reaction times or higher temperatures.

39. How does the steric bulk of the alkyl halide affect the rate of Gabriel synthesis?

The steric bulk of the alkyl halide significantly affects the rate of Gabriel synthesis. As Gabriel synthesis proceeds via an SN2 mechanism, increased steric bulk around the reaction center slows down the reaction. Primary alkyl halides react fastest, secondary are slower, and tertiary often fail to react, instead undergoing elimination.

40. What is the significance of using potassium carbonate in some variations of Gabriel synthesis?

Potassium carbonate is sometimes used in Gabriel synthesis to generate the phthalimide anion in situ. It serves as a mild base to deprotonate phthalimide without being nucleophilic itself. This can be useful when potassium phthalimide is not readily available or when milder reaction conditions are desired.

41. How does the electron-withdrawing nature of the phthalimide group affect the acidity of the N-H bond?

The electron-withdrawing carbonyl groups in phthalimide increase the acidity of the N-H bond. They pull electron density away from the N-H bond, making it easier to lose a proton. This increased acidity is crucial for Gabriel synthesis as it allows for easy formation of the phthalimide anion, which is the active nucleophile in the reaction.

42. Can Gabriel synthesis be used in the preparation of macrocyclic amines?

Yes, Gabriel synthesis can be used in the preparation of macrocyclic amines. This typically involves using a dihalide (or ditosylate/dimesylate) with a long alkyl chain. The phthalimide groups are attached at both ends, and then cyclization is achieved through intramolecular reaction. Subsequent hydrolysis yields the macrocyclic amine.

43. How does the presence of other functional groups on the alkyl halide affect Gabriel synthesis?

The presence of other functional groups can significantly affect Gabriel synthesis. Electron-withdrawing groups can enhance the reactivity of the alkyl halide by making the carbon more electrophilic. However, they may also activate the molecule towards elimination reactions. Electron-donating groups generally decrease reactivity. Groups that can act as nucleophiles or electrophiles may lead to side reactions.

44. What is the role of phase-transfer catalysts in some variations of Gabriel synthesis?

Phase-transfer catalysts can be used in Gabriel synthesis to facilitate the reaction between the ionic phthalimide salt and the organic alkyl halide. They help transfer the phthalimide anion from the aqueous or solid phase into the organic phase where the alkyl halide is dissolved. This can increase reaction rates and yields, especially for less reactive alkyl halides.

45. How does the Gabriel synthesis compare to the Delépine reaction for primary amine synthesis?

Both Gabriel synthesis and the Delépine reaction are methods for synthesizing primary amines, but they differ in several ways:

46. How does the electronic nature of substituents on the phthalimide ring affect the reaction?

Substituents on the phthalimide ring can affect the reaction in several ways:

47. What is the importance of anhydrous conditions in the alkylation step of Gabriel synthesis?

Anhydrous conditions are crucial in the alkylation step of Gabriel synthesis because: