Carboxylic Acid Derivatives - Organic Chemistry - Lecture Notes, Study notes of Organic Chemistry

Download Carboxylic Acid Derivatives - Organic Chemistry - Lecture Notes and more Study notes Organic Chemistry in PDF only on Docsity! 1   Carboxylic Acid Derivatives Nucleophilic Acyl Substitution Nomenclature: In carboxylic acid chlorides, anhydrides, esters and amides, the parent is the carboxylic acid. In each case be sure to include the carbonyl carbon when numbering the chain. This always gets the lowest number. Carboxylic acid chloride (usually abbreviated to acid chloride) acyl chloride: Name acyl group by replacing the parent carboxylic acid ending “-ic acid” with “-yl chloride” (or other halide). CH3CH2 C O Cl parent carboxylic acid: propanoic acid propanoyl chloride CHCH2 C O ClCH2 1234 3-butenoyl chloride CH3 C O Cl acetyl chloride C O Br F p-fluorobenzoyl bromide Carboxylic acid anhydride: replace “acid” with “anhydride”. CH3 C O O C O CH3 acetic anhydride C O O C O benzoic anhydride CH3CH2CH2 C O O C O CH2CH2CH3 propanoic anhydride When the two acyl groups are different, list them in alphabetical order. C O O C O CH2CH2CH2CH3 benzoic pentanoic anhydride Esters: Name the alkyl portion first and then name the acyl portion by substituting “-ic acid” of the parent carboxylic acid with “-ate”. docsity.com 2 CH3 C O OCH2CH3 ethyl acetate CH3CH2CH2 C O OCH3 methyl butanoate CH3 O O CH CH3 CH3 Br OH 1 2 3 4 5 6 isopropyl 5-bromo-2-hydroxy-3-hexenoate Amides: Unsubstituted: Change “-oic acid” of the parent carboxylic acid to “-amide”. CH3 C O NH2 acetamide C O NH2 benzamide CH3 NH2 O CH3 123 4 5 6 3-methyl-2-hexenamide Substituted amides: Name as N-alkyl and N,N-dialkyl derivatives of a parent amide. List the N-alkyl substituents in alphabetical order. If the same N-alkyl substituent reappears as a substituent on the parent chain, the substituent is combined with the N-alkyl substituent as a di-, tri-, etc and its position on the parent indicated by number. C O N CH2CH3 CH3 N-ethyl-N-methylbenzamide N O CH2CH3 CH2CH3 N,N-diethylbutanamide N CH3 CH3 OCH3 1234 56 N,N-3-trimethylhexanamide Nitriles: Add the suffix “-nitrile” to the name of the parent hydrocarbon chain that includes the carbon of the nitrile group itself. Nitriles can also be named by replacing the “-ic acid” or “-oic acid” with “-onitrile”. CH3CH2CH2 C N 1234 butanenitrile or butanonitrile CH3 C N ethane nitrile acetonitrile C N benzonitrile CH3 CH CH3 CN 2-methylpropanenitrile (or common name; isopropyl cyanide) Reactivity Order: docsity.com 5 For Acid Anhydrides: oxygen is more electronegative than chlorine (3.44 v. 3.16) and so withdraws electrons from the carbonyl carbon inductively (i.e. through the bond) but oxygen is a first row element and the C-O bond is considerably shorter than the C-Cl bond. Consequently there is much better overlap of the oxygen lone pair with the π-orbital of the carbonyl. But since there are two carbonyl carbons competing for the oxygen lone pair, the lone pair donation (resonance effect) is diluted. R C O O C O R' R C O- O C O R' R C O O C O- R' For thioesters: Sulfur is a third row element, like chlorine, and so it is considerably larger than oxygen. The C-S bond is relatively long and this makes for poor overlap of the lone pair 3p orbital and the π-orbital of the carbonyl. But thioesters are less reactive than acid chlorides and anhydrides due to the fact that the sulfur is considerably less electronegative than oxygen and chlorine. The inductive electron withdrawing effect of the sulfur is less than that of oxygen or chlorine due to the decreased electronegativity of sulfur versus oxygen (2.58 v. 3.44). For esters: The oxygen substituent of esters is an overall electron-donating group. There is the electron withdrawing effect due to the greater electronegativity of oxygen as compared to carbon but this is outweighed by the electron donating effect of the oxygen lone pair due to resonance. R C O O R' inductive effect withdraws electrons resonance effect donates R C O- O R' In esters, the electron donation of the oxygen lone pair is stronger than the eelctron withdrawal due to the greater electronegativity of oxygen as compared to carbon. For amides: Nitrogen is less electronegative than oxygen (3.04 v. 3.44) but is still more electronegative than carbon (2.55) so in amides there is still an electron withdrawing inductive effect through the C-N bond but there is a much larger electron donating effect due to resonance donation of the nitrogen lone pair into the carbonyl π-orbital. R C O N R' inductive effect withdraws electrons slightly strong resonance effect donates electrons R C O- N R' R'' R'' docsity.com 6 The strong resonance donation gives the carbon-nitrogen bond in amides lots of double bond character. The C-N bond in amides is much shorter than a normal C-N bond. R C H H N R' R'' 1.47 A° R C O N R' R'' 1.35 A° There is a considerable barrier to rotation around the C-N bond since there is a lot of sp2 character for the amide nitrogen. All of the three bonds of the amide lie in the same plane. Eact = 75 - 85 Kj/mol (18-20 Kcal/mol)C R O N R' R'' C O N R' R'' R Carboxylate anion: This is also stabilized by resonance. The negatively charged oxygen is a powerful electron donor and so a Carboxylate anion behaves very differently from the other carboxylic acid derivatives under discussion. The carbonyl carbon is not electrophilic and is not attacked by nucleophiles. R C O O- R C O O- Again, to convert one carboxylic acid derivative into another one, the reaction is feasible only if the new derivative lies BELOW it in reactivity or, in other words, only if the conversion is from a less stable carbonyl to a more stable one. A very useful way to remember the reactivity order is to consider the leaving group ability of the X group. As we discussed above, the slow step (rate determining step) of the reaction is the attack on the carbonyl and loss of the leaving group is fast but the leaving group ability of X does correlate with the overall rate of the reaction. And so we can remember the reactivity order by considering which is the better leaving group. As we know, the more stable the anion – i.e. the weaker the base – the better the leaving group. docsity.com 7 R C O Cl R C O O C O R' R C O S R' R C O O R' R C O N R' R'' > > > > >> R C O O- Leaving Group Cl- -O C O R' -S R' -O R' -N R' R'' O-2 (does not exist)Conjugate Acid HO C O R' HS R' HO R' HN R' R'' HCl pKa -6 5 10 16 36 weakest acid, Strongest base worst leaving group least reactive derivative strongest acid, weakest base best leaving group most reactive derivative This is simply a mnemonic, a useful way to remember the reactivity order but you can see that there is good correlation between the reactivity and leaving group ability. Acid chlorides Preparation Acid chlorides are extremely reactive and are generally prepared in situ from carboxylic acids by heating in a solution of thionyl chloride. The thionyl chloride is generally used in excess as the solvent and when the reaction is finished the excess is removed by distillation, leaving behind the moisture sensitive and highly reactive acid chloride. Aqueous workups are to be avoided since the acid chlorides react rapidly with water to reform the carboxylic acid. CH3 C O OH Cl S O Cl strong Lewis acid Cl S O Cl + CH3 C O H O S ClCl O- CH3 C O H O S Cl O Cl- CH3 C O H O S Cl O Cl CH3 C O H Cl Cl- CH3 C O Cl+HCl+SO2 Reactions of Acid chlorides Acid chlorides are the most reactive of the carboxylic acid derivatives and can therefore be used to prepare all of the other derivatives: (1) anhydrides (2) thioesters (3) esters (4) amides (5) carboxylic acids. docsity.com 10 (4) Hydrolysis of Acid Chlorides Acid chlorides are easily hydrolyzed by water to give the carboxylic acid. This is not a useful reaction synthetically since acid chlorides are produced from carboxylic acids but it is a reaction that we must be aware of and usually try to avoid. CH3 C O Cl + CH3 C Cl O- O H H CH3 C Cl O O H H CH3 C O O H neutral tetrahedral intermediate Cl- proton transfer occurs to give the neutral tetrahedral intermediate O H H H O H O H H H O H H O H H H+ Anhydrides After acid chlorides, the next most reactive derivatives are the anhydrides. They can be used to form the esters and amides and are also subject to hydrolysis. It is best to think of acid chlorides and anhydrides as reagents used for the preparation of the more stable end products, the esters and the amides. Preparation In the laboratory anhydrides are usually prepared from acid chlorides, as we have just seen. CH3 C O Cl + HO C O N CH3 C O O C + N H Cl-O Other common derivatives are prepared by special methods on an industrial scale. These include CH3 C O O C O CH3 acetic anhydride O O O phthalic anhydride O O O maleic anhydride docsity.com 11 Reactions of Anhydrides Since a nucleophile can attack either carbonyl, symmetrical anhydrides are usually used so as to give one product. (1) Preparation of Esters (a) We can use neutral alcohols. With the neutral alcohols we usually use acid catalysis to activate the carbonyl carbon of the anhydride to nucleophilic attack since the neutral alcohol is a relatively weak nucleophile. Acid catalysis increases the rate of formation of the tetrahedral intermediate. R C O O C O R + HOR' cat. H+ R C O O R' HO C O R+ For example: CH3 C O O C O CH3 O CH2CH2CH3 H H OCH3CH2CH2 H CH3 C O O C O CH3 H OCH3CH2CH2 H CH3 C O O C O CH3 H O CH2CH2CH3 CH3CH2CH2OH CH3 C O O C O CH3 H O H CH2CH2CH3 HOCH2CH2CH3 CH3CH2CH2O C O CH3+CH3 C O O OCH3CH2CH2 H H CH3 C O OH (b) Ester can also be formed from anhydrides in basic conditions using alkoxides. + OCH3 C O O C O CH3 CH3 C O O C CH3 O O O C O CH3 + CH3 C O O (2) Amide formation from anhydrides Primary and secondary amines react with anhydrides to give amides. No catalysis is needed, since amines are basic and good nucleophiles. Use of acid would protonate the amine rather than the carbonyl carbon, making the amine non-nucleophilic. docsity.com 12 +CH3 C O O C O CH3 N H H CH3 C O O C O CH3 NH H PhNH2 H3+NPh CH3 C O O C O CH3 N H H H2NPh CH3 C O N H +CH3 C O O H3+NPh (3) Hydrolysis Anhydrides are not stable in water and are converted back to the parent carboxylic acids. The reaction is generally slow at room temperature and is accelerated by heat. O O O + O H H C O O O O H H OH2H O H H C O O O O H H C O O- C O OH H2O H O H H C O OH C O OH Esters Preparation: (1) As we saw, esters can be prepared directly from carboxylic acids and alcohols under conditions of acid catalysis. C O OH + H2SO4 C O OCH3 H2OHOCH3 + (2) From acid chlorides docsity.com 15 (3) Hydrolysis of esters to carboxylic acids in acidic or basic conditions. R C O OR' Aqueous acid or aqueous base R C O OH + R'OH (a) Ester hydrolysis in acidic conditions is fully reversible and is the exact reverse of ester formation. We drive the reaction to the right in favor of hydrolysis by using an excess of water. CH3 C O OCH3 + H O H H H2O CH3 C O OCH3 H H O H CH3 C O OCH3 H O HHH2O H O H H CH3 C O OCH3 H O H H H2O CH3 C O OH + HOCH3 (b) Ester hydrolysis can also take place in basic conditions using aqueous sodium hydroxide. This reaction is called saponification (from the Latin sapon for soap because the basic hydrolysis of animal fat was a traditional way of making soap). One advantage of the basic hydrolysis is the reaction is irreversible. The initial carboxylic acid formed is irreversibly deprotonated by the basic hydroxide solution. To isolate the neutral carboxylic a final protonation step is required. The pH is made acidic by the addition of aqueous HCl. CH3 C O OCH3 + Na+ -OH H2O heat CH3 C OCH3 OH O- CH3 C O O + -OCH3H pKa 5 CH3 C O O- + HOCH3 pKa 16 Final step is irreversible and this drives the equilibrium to the right in favor of hydrolysis. weaker acid stronger acid H3O+ H2OCH3 C O OH Note that cleavage always occurs between the carbonyl carbon and the oxygen, not between the alcohol carbon and the oxygen. docsity.com 16 R C O O R' Cleavage is always of this bond Therefore cleavage of esters with optically active alcohols results in retention of configuration of the alcohol moiety. C O O C CH3 H CH2CH3 Na+ -OH H2O -OH C O C CH3 H CH2CH3 O- O H C O -O C CH3 H CH2CH3 O H + C O O HO C CH3 H CH2CH3+ S-configuration S-configuration (4) Reaction of Esters with Grignard and organolithium reagents. Grignard and organolithium reagents react twice with esters to give tertiary alcohols in which two of the substituents are the same. C O OCH3 2 BrMgCH2CH3 THF C OCH3 O CH2CH3 hemi-acetal, unstable C CH2CH3 O 2 BrMgCH2CH3 C O CH2CH3 CH2CH3 MgBr+ H3O+C HO CH2CH3 CH2CH3 Thioesters docsity.com 17 Preparation: Thioesters can be prepared from acid chlorides or anhydrides using the same conditions as discussed above for esters. From acid chlorides: R C O Cl + HSR' pyridine R C O SR' + NH Cl R C O Cl + Na+ -SR' R C O SR' + NaCl C O Cl + Na+ -SCH2CH3 C O- Cl SCH2CH3 C O SCH2CH3 From anhydrides R C O O C O R + HSR' heat R C O SR' + HO C O R Reactions Thioesters will react with alcohols, alkoxides and amides. They see limited use in laboratory synthesis but are very important in biological systems. R C O SR' + Nu H R C O Nu + HSR' C O SCH2CH3 + HOCH3 HCl C O OCH3 + HSCH2CH3 Thioesters are about as reactive as esters even though the ΔG for hydrolysis is more negative. The rates for hydrolysis are about the same as for esters. But thioesters are much more reactive toward amine nucleophiles than esters. This helps to account for the importance of thioesters in biochemistry. Many biochemical reactions involve acyl transfer. The thioester, acetyl coenzyme A transfers acyl groups to alcohols, amines and other nucleophiles. docsity.com 20 (3) thioesters, (4) from esters. Since an acid is produced when acid chlorides or anhydrides are used, an extra equivalent of the amine is often added so as to neutralize this acid. If the amine is expensive, another base may be added. R C O Cl + H N R' R' R C O N R' R' R' = H, alkyl or aryl R C O O C O R + HCl + H N R' R' R C O N R' R' + R C O OH R C O OR'' + H N R' R' R C O N R' R' + HOR" Cyclic amides or lactams can be formed. NH O NH O NH O α β γ δ α β γ α β δ-lactam γ-lactam β-lactam The β-lactams are very important in medicinal chemistry since they are the key reactive functional group in the penicillin antibiotics. N S H N O CH2 O CH3 CH3 CO2H penicilin G N H N O CH O S CH3 CO2H H2N cephalosporin The 4-membered ring lactam is much more reactive than normal lactams due to angle strain. It undergoes a ring opening reaction when attacked by a sulfhydryl group of one of the bacterial enzymes involved in cell wall synthesis. Humans do not have this enzyme and therefore are not harmed by the drug. The penicillin is a “suicide inhibitor” because it docsity.com 21 forms an irreversible covalent bond with the target bacterial enzyme, shutting down its function and eventually leading to death of the bacterial cell. N S H N O Ph O CH3 CH3 CO2H + HS Enzyme N S H N O Ph CH3 CH3 CO2H -O S EnzymeH N S H N O Ph CH3 CH3 CO2H -O S Enzyme H S C O Enzyme HN N H S O Ph CH3 CH3 CO2H Covalent adduct of enyme and penicilin Reactions of Amides Because amides are the least reactive of the carboxylic acid derivatives, the only significant reactions they undergo are hydrolysis. This occurs under acidic or basic conditions. R C O N R' R' Acid or base heat R C O O H + H N R' R' Acidic Conditions CH3CH2 C O N H H + H O H H H2O CH3CH2 C O N H H H H2O CH3CH2 C N H H H O HH O H2O H O H H CH3CH2 C N H H H O H O H CH3CH2 C O OH+H N H H H O H H H N H H H docsity.com 22 Note that in the first step, protonation of the amide occurs on the carbonyl oxygen, not on the nitrogen. Protonation on the carbonyl allows for resonance stabilization of the resulting cation by the nitrogen lone pair. If protonation were to occur on the nitrogen, no such resonance stabilization by oxygen lone pair would be possible. CH3CH2 C O N H H H CH3CH2 C O N H H H resonance stabilization from the nitrogen lone pair CH3CH2 C O N H H H No resonance stabilization possible from the oxygen lone pair since the carbon would then have five bonds. Basic conditions The final step is irreversible deprotonation of the carboxylic acid in the basic conditions. To isolate the neutral carboxylic acid, CH3CH2 C O N H H + Na+ -OH CH3CH2 C O- N H HOH H2O H O H CH3CH2 C O O H + NH3 Na+ -OH CH3CH2 C O O- Add H3O+ CH3CH2 C O O H Nitriles Preparation (1) Nitriles can be prepared by means of an SN2 reaction of cyanide anion with alkyl halides. R CH2 X + M + -:CN R CH2 CN (2) By reaction of cyanide anion with an aldehyde or ketone to form the cyanohydrin. docsity.com