Reaction of Amines with Acid Derivatives| Amide Preparation & Mechanism_MDCAT скачать в хорошем качестве

Reaction of Amines with Acid Derivatives| Amide Preparation & Mechanism_MDCAT

*Comprehensive Guide to Amine Reactions with Acid Derivatives and Amide Synthesis (MDCAT Focus)* This guide explains the core concepts of how amines react with carboxylic acid derivatives to form amides, a fundamental topic for the MDCAT. *1. Fundamental Reaction Principle* Amines act as nucleophiles and react with carboxylic acid derivatives through a process called *Nucleophilic Acyl Substitution**. The amine attacks the electrophilic carbonyl carbon of the acid derivative, leading to the formation of an amide. The ease of this reaction depends heavily on the nature of the **Leaving Group* attached to the carbonyl. The standard reactivity order is: *Acid Chlorides (Acyl Chlorides) is greater than Acid Anhydrides is greater than Esters is greater than Amides is greater than Carboxylic Acids.* This order is determined by how good the leaving group is (e.g., Cl- is excellent, R'O- is poor). *2. The Core Mechanism: Step-by-Step* The mechanism is a two-step *Addition-Elimination* process. Using an acyl chloride and a primary amine as an example: *Step 1: Nucleophilic Attack* The lone pair on the nitrogen of the amine attacks the carbonyl carbon of the acid chloride. This breaks the C=O pi bond, forming a tetrahedral intermediate with a negative charge on oxygen. *Step 2: Elimination of the Leaving Group* The unstable tetrahedral intermediate collapses. The carbonyl C=O bond reforms, and the chloride ion (Cl-) is expelled as the leaving group. This results in the formation of the amide product. *Important Note:* The reaction produces HCl. Therefore, two equivalents of amine are often used: one to act as the nucleophile and the second to neutralize the acid, forming an ammonium salt. Alternatively, an added base like pyridine can be used. *3. Reactions with Different Acid Derivatives* *With Acyl Chlorides:* The most reactive. Reaction is fast at room temperature. Byproduct: HCl. *With Acid Anhydrides:* Very reactive. The leaving group is a carboxylate, leading to a carboxylic acid byproduct. *With Esters:* Less reactive. Requires heat. The leaving group is an alkoxide (RO-), leading to an alcohol byproduct. *With Carboxylic Acids:* Does *not* proceed easily by simple mixing. The initial acid-base reaction forms an ammonium salt. To form an amide, you need: *Strong heating* to dehydrate the salt, OR A *coupling agent* like DCC (Dicyclohexylcarbodiimide). DCC activates the acid, allowing the amine to attack and form the amide. This is a crucial modern lab method. *4. Key Concepts for MDCAT Mastery* *Amide Resonance & Basicity:* The nitrogen in an amide is much less basic than in a normal amine. This is because its lone pair is delocalized (in resonance) with the carbonyl group. This gives the C-N bond partial double-bond character, making it rigid and planar—a critical feature in protein structure (peptide bonds). *Leaving Group Ability:* This is the central concept governing the reactivity trend. A good leaving group (like Cl-) makes the elimination step fast and the overall reaction favorable. *Biological Relevance:* The formation of a *peptide bond* (an amide linkage) between amino acids is the key reaction in protein synthesis. It follows a similar nucleophilic acyl substitution mechanism using an activated ester. *5. Summary Table for Quick Revision* | Acid Derivative | General Formula | Reactivity | Key Byproduct | Typical Conditions | |-----------------|-----------------|------------|---------------|-------------------| | Acyl Chloride | R-COCl | Very High | HCl | Room temp, base present | | Acid Anhydride | (R-CO)2O | High | Carboxylic Acid | Mild heating possible | | Ester | R-COOR' | Moderate | Alcohol (R'OH) | Heating, often catalytic | | Carboxylic Acid | R-COOH | Low | H2O | Requires DCC or strong heat | *6. MDCAT Focus and Study Tips* Expect questions on: Drawing or recognizing the nucleophilic acyl substitution mechanism. Predicting the major product from given reactants. Ranking derivatives based on reactivity. Understanding why direct acid+amine reaction fails and how DCC solves it. Explaining the unique properties of amides (low basicity, resonance). *Study Strategy:* Start by mastering the mechanism with acyl chlorides. Then, apply the same two-step logic to other derivatives, simply changing the leaving group. Practice writing reactions for each derivative type and understand the role of the base.