MD 4. Carboxylic Acid Derivatives: Nucleophilic Substitution Reactions

What are the differences in the way ketones, carboxylic acids and esters react with nucleophiles?

• ketones react with nucleophiles under nucleophilic addition reactions

• Esters react with nucleophiles under a nucleophilic substitution reaction - the OR group is removed and replaced with the nucleophile, leaving the carbonyl on

• Carboxylic acids react under competitive deprotonation to form RCOO- and NuH - although nucleophilic acyl substitution can occur sometimes

What are leaving groups? What are the ‘best’ leaving groups?

• leaving group accept a lone pair of electrons as the bond between it and its neighbour is broken

• best leaving groups are neutral molecules, water, and stable ions, Cl-

How does pK_a link to leaving group ability?

• the more stable the ion is, the better it will be as a leaving group and the larger the equilibrium constant will be - the equilibrium constant is the acid dissociation constant, K_a

• pK_a = -log10 (K_a)

• Therefore, the more stable A- is, the higher the K_a and the smaller the pK_a so a lower pK_a value for the conjugate acid, HA, makes A- a better leaving group

What is the relative reactivity for aldehydes, ketones, esters?

• esters react slower than ketones and aldehydes as the Or group is a +M mesomeric group making the C less delta positive

• And aldehydes react the quickest still due to only one +I effect and less steric hinderance

• And ketones are in the middle with two +I effects causing the C to be slightly less delta positive and there to be more steric hinderance with two R groups

What is the relative reactivity of carboxylic derivatives

• fast nucleophilic acyl substitution needs a strong nucleophile and electrophilic carboxylic derivatives.

• based on the electrophilicity of the carbon, the most to least reactive is: acyl chloride, acid anhydride, ester, and lastly amide is the least reactive.

• acyl chlorides have a very strong -I effect from the Cl, making the carbon more positive and more reactive

• acid anhydrides have a weak +m effect and a much stronger -I effect as there is electron resonance from the central O atom making a more positive C

• esters have a +m effect making the carbon a less positive

• Amides have a strong +M effect making the carbon less positive.

Outline the reaction and mechanism for the esterification of a carboxylic acid

• carboxylic acid + alcohol = ester + water

• uses an acid catalyst

• All steps are reversible however so there are two ways to push the equilibrium towards ester formation: 1) use excess alcohol and 2) remove water from reaction mixture as it is formed

• acid H+ catalyst reacts with carboxylic to make a reactive electrophile that reacts with the alcohol, then the ROH group is deprotonated, the other OH group reacts with H+ to form H2O+ on the molecule, lone pair from the other OH is moved to this H2O, which is our leaving group

• the proton attached to the O on the newly formed C=O bond is then removed and this is the regeneration of our catalyst

What reactions (5) with what conditions can acyl chlorides undergo?

• they can undergo the widest nucleophilic reactions as the most reactive

• hydrolysis - reaction with water to form carboxylic acid and HCl

• alcoholysis - reaction with alcohol to form an ester and HCl

• Grignard reagent substitution and then addition - makes ketone intermediate through substitution of the reagent R group replacing the Cl and then RMgX and H+ is added to undergo addition and form a tertiary alcohol

• aminolysis - reaction with 2NH3 to form a primary amide and NH4Cl

• Reduction - NaBH4 reducing agent, forms aldehyde intermediate, then reacted with NaBH4 and H+ to reduce to a primary alcohol

What reactions (4) with what conditions can acid anhydrides undergo?

• nucleophile attacks the C=O and the RCO2 acts as a leaving group

• hydrolysis - addition of water - forms two carboxylic acid molecules

• alcoholysis - addition of alcohol to form an ester and a carboxylic acid

• reduction - LiAlH4 reducing agent to source H-, forms an aldehyde and carboxylate ion intermediates, then add LiAlH4 and H+ to form a primary alcohol.

• Aminolysis - Addition of two ammonia molecules (2NH3) to form a primary amide and an ionic H4N+OCOR molecule

What reactions (4) with what conditions can esters undergo?

• Nucleophile attacks C=O and RO- acts as leaving group

• reaction with ammonia (NH3) to form a primary amide and an alcohol

• Reaction with LiAlH4 to form aldehyde and OR- intermediates, react with more LiAlH4 and H+ to form a primary alcohol and another alcohol

• Grignard Reagent - Reacts with RMgX to substitute the R group in and make a ketone and OR- intermediate, react with another RMgX molecule and H+ to form a tertiary alcohol and another alcohol

• hydrolysis/de-esterification - React with water and H+ (or base hydrolysis with water, OH- and then H+) to form an alcohol and carboxylic

What reactions (2) with what conditions can amides undergo?

• only undergo a couple of reactions as they are least reactive of the carboxylic derivatives as the carbonyl is a poor electrophile

• hydrolysis - water and H+ or base hydrolysis with water, OH- and then H+, under a high temp with a concentrated acid/base to form a carboxylic acid

• Reducing agent addition reaction - LiAlH4 then H+ added to form a primary amine