Nucleophilic Substitution in Carboxylic Acids: Reactions, Mechanisms, and Applications, Study notes of Chemistry

Download Nucleophilic Substitution in Carboxylic Acids: Reactions, Mechanisms, and Applications and more Study notes Chemistry in PDF only on Docsity! 1 CARBOXYLIC ACIDS and their Derivatives –Nucleophi l ic Acyl substitut ion - Review the nomenclature for these compounds in your textbook O R Z •• O – R Z •• O – R Z - the basicity of Z determines the relative stability of carboxylic acid derivatives; thus, the order of stability is: O R Cl O R O O R OH O R OR O R O R NR'2 < < ~ < acid chloride anhydrides carboxylic acids esters amides (R' = H or alkyl) - the order of reactivity is the reverse (the better the leaving group, the more reactive RCOZ is in nucleophilic acyl substitution): O R Cl O R O O R OH O R OR O R O R NR'2 > > ~ > acid chloride anhydrides carboxylic acids esters amides (R' = H or alkyl) - based on this order of reactivity, more reactive acyl compounds (acid chlorides and anhydrides) can be converted to the less reactive ones (carboxylic acids, esters, and amides) but the reverse is usually not true. Why? O R Z Nu C O R Nu Z 2 possible leaving groups For a reaction to occur, Z must be a better leaving group than Nu - Formation of Acid Chlorides Acid chlorides (or bromides) are extremely reactive. However, they are easily prepared from carboxylic acids by two common methods: 1) Treatment with thionyl Chloride (SOCl2): 2 - the poor leaving group, OH, is transformed into a better leaving group in this process- see Mechanism 22.5. 2) Treatment with oxalyl chloride (a much nicer reaction!): cat. DMF This reaction is believed to proceed via the mechanism below: Why make acid chlorides? They are the fastest way to get to any other carboxylic acid derivative, or to a number of other carbonyl compounds: 5 O R OH R'OH as solvent HCl or H2SO4 catalyst O R OR' + H2O -To drive the reaction to completion, excess alcohol must be used or water must be removed as it is formed. See Mechanism 22.6. - esterification of a carboxylic acid occurs in the presence of an acid but not in the presence of a base (since a carboxylate ion results under basic conditions). 6 performed on an ester rather than an acid. Finally, esters are very common in nature and thus are often the final goal of synthesis O R OH O R OMe MeOH/H2SO4 1. MeMgBr 2. H2O OH R Me Me 1. MeMgBr 2. H2O O R OH + CH4 reverse of Fischer Esterification of carboxylic acids (see mechanism 22.8). 0 | AP x (in DMF, 40°C) OH Oo oe KOH / HO jag OH 96% yield 1008C 100% yield Transesterification or “Ester-Transposition” - this term refers to swapping one “OR" portion of an ester for another, as shown in the schemes below; this reaction can take pla ni ither acidic or basic conditions: 0 0 ow EtOH / H* OEt Oo ‘OMe _NaOEt aa excess) These reactions are typically run ina LARGE excess of the alcohol/ alcoholate to be“swapped” - this is required because as the reaction proceeds, large amounts of the initial alcohol are produced, Let’s look at the mechanisms: Nitriles Preparation Primary alkyl nitriles are generally prepared by the reaction of potassium or sodium cyanide with a primary alkyl halide. Secondary and tertiary nitriles cannot be formed by this route, and are thus made by the dehydration of an amide (usually with SOCI,, but occasionally also with P2Qs): KCN SOCL ~ 7 2 2N R B R Cs, Sa = " °N R NH, heat are Reactions As you have already seen that nitriles can be hydrolyzed to amides and carboxylic acids quite readily. Your text provides a good description of the mechanism. + HO" ron 2. p-coox RCN ==> R-CONH, H2y R-cooH H,O H,0 210° 130" 120° Otherwise, nitriles behave quite similarly to the carbonyl compounds. The nitrile carbon is electrophilic, and the nitrogen can easily stabilize a negative charge. The nitrile nitrogen is also easily protonated. reduction: Like amides, nitriles are reduced with LiAIH, to primary amines. The reaction is quite clean, usually affording the amine in >80% yield. However, because nitriles are often made from amides, it is often easier to convert the amide to the amine, rather than go through the nitrile. The only real exception to this is in the preparation of amino acids, which we shall not have time to discuss. By using a weaker reducing agent, it is possible to stop reduction after the addition of only one hydride, leaving an /mine. As you recall, imines are usually prepared by reacting an amine with a ketone or aldehyde - it is not surprising, then, that this imine can be hydrolyzed to an aldehyde. Again remember that there are usually easier ways to make aldehydes: 1) LiAIK, poe Ne ac 2) H0* ‘SN 1) DIBAL-H (-78°C) R H 2)H,0 yt And yes, you can add Grignard reagents to nitriles. In this case, you also end up with an imine which is in this case hydrolyzed to a ketone. And again remember, there are other ways to make the same ketones (i.e. you only have to remember one route...) 10 H,0* /H, end ~~ pe swte ® baie 5 son oe who 228 = ye 11