Ch. 21: CARBOXYLIC ACID DERIVATIVES AND NUCLEOPHILIC ACYL SUBSTITUTION REACTIONS Nomenclature of Carboxylic Acid Derivatives:

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1 h. 21: ABXYLI AID DEIVATIVES AND NULEPILI AYL SUBSTITUTIN EATINS Nomenclature of arboxylic Acid Derivatives: arboxylic acids "-oic acid" Examples: 3 2 Propanoic acid yclohexanecarboxylic acid 1 arboxylate salts (metal) "-oate" - M Examples: 3 2 Na Na Sodium propanoate Sodium cyclohexanecarboxylate Esters (alkyl, aryl) "-oate" ' Examples: Ethyl propanoate Ethyl cyclohexanecarboxylate Anhydrides Examples: Acid (acyl) chlorides Examples: Propanoic anhydride l 3 2 l Propanoyl chloride "-oic anhydride" "-oyl chloride" yclohexanecarboxylic anhydride l yclohexanecarbonyl chloride Amides Examples: Nitriles Examples: N'" 3 2 N( 3 ) 2 N,N-Dimethylpropanamide N 3 2 N Propanenitrile (N,N-alkyl, aryl) "-amide" "-nitrile" yclohexanecarboxamide N yclohexanecarbonitrile

2 Nucleophilic Acyl Substitution arbonyl compounds undergo addition reactions with nucleophiles because they have no leaving groups: ' Nu (or Nu) slow ' Nu ( Nu) Stable Tetrahedral Intermediate --No leaving group ' Nu ' 2 Nu 2 Acyl compounds, which do have leaving groups, react with similar nucleophiles by substitution: Nu X slow Nu X fast Nu X Unstable Tetrahedral Intermediate --as leaving group (X) eactivity of Acyl ompounds The more electronegative the leaving group, the more reactive toward nucleophilic substitution the acyl compound is. This is a result of increasing positive charge at the acyl carbon, which makes it more attractive to electron-rich nucleophiles. l ' N'" eactivity: Acid chloride Anhydride Ester Amide > > > Usual direction of conversion

3 3 All of the acyl compounds are more reactive than the corresponding alkyl compounds (e.g. l >> 2 l) because of the polarization of the = bond (and the resulting positive charge on the acyl carbon), the ability to shift negative charge to oxygen in the tetrahedral intermediate, and less steric hindrance at the sp 2 trigonal acyl carbon, relative to the sp 3 tetrahedral alkyl carbon. l Nu is less crowded than l Nu onversion among acyl derivatives is generally from the more reactive derivatives to the less reactive, more stable ones. (There are exceptions, however) As a consequence, acid chlorides, the most reactive acyl compounds, are very important in the preparation of other carboxylic acid derivatives. Acid chlorides can be made readily from the carboxylic acids, themselves. A number of reagents, of which thionyl chloride (Sl 2 ) is the most common, can be used for this purpose. ther reagents include phosphorus pentachloride (Pl 5 ), and, for preparation under especially mild conditions, oxalyl chloride (ll): Examples: Sl 2 l S 2 l l l Pl 5 l Pl 3 l pyridine l l Na l (mildest) 2 Nal

4 4 These acid chlorides, in turn, can be converted to other carboxylic acid derivatives by reaction with appropriate nucleophiles: l l ' ' l Ester l Anhydride 2 N 3 N 4 l Amide N'" Na Nal N'" Each of these reactions is a typical Nucleophilic Acyl Substitution in which the very reactive acid chloride reacts with a relatively mild nucleophile. For example: l 2 3 l 2 3 l 2 3 l The mechanism is essentially the same for each of the other reactions of acid chlorides, the only differences being the specific nucleophiles involved.

5 5 eduction of Acid hlorides In addition to conversion to other acyl derivatives by nucleophilic substitution, we have seen that acid chlorides can be reduced to aldehydes. Lithium aluminum hydride is too reactive to be useful for this purpose (the reduction would go all the way to the primary alcohol). owever, its potency can be reduced by prior reaction with three moles of tert-butyl alcohol: LiAl 4 3 ( 3 ) > LiAl[ ( 3 ) 3 ] l LiAl[ ( 3 ) 3 ] > LiAll[ ( 3 ) 3 ] 3 This hydride reducing agent will not reduce other groups such as N 2, esters, etc. n a large scale, the reduction can be accomplished by the osenmund reduction: Pd/BaS 4 l > l ethyl acetate Preparation of Ketones from Acid hlorides Although ketones cannot easily be prepared by reaction of Grignard reagents with acid chlorides, because the ketone, itself, reacts with Grignard reagents, they can be synthesized through the use of other organometallic reagents. l ' MgX (or ester--cheaper) MgX l ' MgXl ' The ketone reacts with a second equivalent of Grignard reagent ' MgX MgX ' ' ' ' Will get the 3 alcohol K, but it is difficult to stop at the ketone. BUT: l ' 2 uli or ' 2 d ' Lil 'u The ketone does not react readily with ' 2 uli or ' 2 d.

6 Acid Anhydrides arboxylic acid anhydrides are formally derived by elimination of one mole of water from two moles of the acid: For certain cyclic anhydrides, this is actually a useful method of preparation: Phthalic acid For the above reaction to be successful, the dicarboxylic acid must give a cyclic anhydride with five or six atoms in the ring. More generally, anhydrides can be prepared by reaction of a carboxylic acid with an acid chloride: l 200 This is another example of nucleophilic acyl substitution in an acid chloride. Anhydrides can also be prepared by treatment of a carboxylic acid with acetyl chloride or acetic anhydride, and distilling off acetic acid from the resulting equilibrium mixture. This method is most successful for preparation of relatively high-boiling anhydrides, from which the acetic acid can be separated by distillation. N 2 3 N 2 2 Phthalic anhydride l N

7 eactions of Acid Anhydrides The substitution reactions of anhydrides are similar to those of acid chlorides, although the anhydrides are less, reactive, and hence their reactions may be more easily controlled. This is especially important in the use of acetic anhydride, since acetyl chloride is one of the most reactive acid chlorides. Aniline 3 3 Note that of the two acyl groups in the anhydride, N only one is used in substitution; this is less efficient than with N 3 3 Acetanilide (N-Phenylethanamide) 7 N 3 3 the acid chloride. As a consequence, of the anhydrides of monocarboxylic acids, only acetic anhydride is commonly used, because it can be manufactured cheaply. The cyclic anhydrides of dicarboxylic acids are also in common use, where substitution of only one of the two acyl groups may be desired * This ester, which is also a carboxylic acid, may be reacted with an optically active amine (base) to form a diastereomeric salt in order to separate the enantiomers. ( 3 ) ( 2 ) Succinic acid Succinic anhydride B 3 78 Ethyl 4-hydroxybutanoate * ydroxybutanoic acid

8 Esters Preparation: Esters can be prepared in a number of ways: S N 2 Substitution of Alkyl alides S N 2 3 l 2 3 Na Nal 2 Sodium acetate Benzyl chloride Benzyl acetate eaction of Acids with Diazomethane 8 ' Diazomethane reacts with carboxylic acids to give the methyl esters under very mild conditions, but 2 N 2 is very toxic and explosive. It is used only in small-scale preparations: 2 N 2 3 N 2 By eaction of Alcohols with Acid hlorides or Anhydrides l By Direct, Acid-catalyzed eaction of arboxylic Acids with Alcohols Many simple esters can be prepared by heating carboxylic acids with an excess of the alcohol in the presence of an acid catalyst (often 2 S 4 or l not aqueous hydrochloric acid) N catalyst & base sec-butyl benzoate 3 (XS) 3 2 N l This is an example of an acid-catalyzed nucleophilic acyl substitution. The catalyst is necessary because carboxylic acids are much less reactive than acid chlorides or anhydrides, and will not otherwise react with the weakly nucleophilic alcohols.

9 Mechanism: All steps in the above mechanism are reversible, and therefore the overall reaction is also a reversible equilibrium, which may be driven to completion by removal of generated water, and by use of a large excess of the alcohol (as solvent). For this reason, the reaction is almost entirely used for the preparation only of esters of relatively simple, cheap alcohols. n the other hand, since all steps are reversible, a large excess of water will drive the equilibrium back to carboxylic acid and alcohol, resulting in acid-catalyzed hydrolysis of the ester. The mechanism of this hydrolysis is just the same as the esterification, only in the opposite direction

10 eactions of Esters Acid-atalyzed ydrolysis We have just seen that the mechanism for the acid-catalyzed hydrolysis of esters, 10 acyl bond ' ' is just the reverse of the mechanism for acid-catalyzed esterification of a carboxylic acid in alcohol solution. It is the acyl carbon-oxygen bond that is broken. Evidence for this has been obtained from oxygen-18 labeling experiments: This is the case for most esters, but there are exceptions, particularly when the alkoxy alkyl group can form a stable carbocation: Esters of Tertiary Alcohols: ( 3 ) 3 ( 3 ) 3 3 ( 3 ) (3 ) 3 tertiary carbocation Also, Methoxymethyl Ester: hemiacetal of formaldehyde

11 Saponification The hydrolysis of esters can also be carried out under alkaline (basic) conditions. 2 2 ' ' Note: This reaction is NT written as an equilibrium as is the acid-catalyzed hydrolysis. Furthermore, the hydroxide is consumed, and is not a true catalyst. This base-promoted hydrolysis is called "Saponification" (soap forming), because, in fact, this is the reaction that takes place when soap is made from fats and potash or lye. 2 2 ' 3 Na 2 2 Na 2 Na 2 ' 2 " 2 Na 2 " triglyceride glycerol soap (fatty acid triester of glycerol) The salts of fatty acids have a polar, ionic end which is hydrophilic (water loving), and non-polar, hydrophobic end (water avoiding). This is typical of surfactants (surfaceactive agents), which can be symbolized as at right. When dissolved in water, such surfactants first collect at the water/air interface in a monolayer, with the hydrophilic end in the water, and the hydrophobic end in the air: This interferes with hydrogen-bonding between the water molecules at the surface, reducing surface tension, and allowing the water to better wet surfaces to be cleaned. When more surfactant is added, a point is reached where no additional molecules can fit on the surface as above. Micelles then form within the solution: These micelles have a fatty, hydrophobic interior that can catch up and take into solution greasy soils. polar, hydrophilic end non-polar, hydrophobic end air water 11 micelle

12 12 These properties account for soap s cleaning ability If we stretch out the micelle, we see that it is closely related to the lipid bilayer that makes ups cell walls. The lipids in cell walls also have hydrophilic and hydrophobic ends: cell exterior (aqueous) cell wall cell interior (aqueous) Mechanism of Saponification: The mechanism is straight-forward: ' ' ' ' The last step in the above reaction is responsible for the effective irreversibility of saponification. This reaction is the earliest known, and most intensively studied of the nucleophilic substitutions of acyl compounds. It is on the basis of this mechanism that the mechanism of other acyl substitutions were proposed. Let's consider some alternative mechanisms, and examine the experimental evidence. S N 2-like: ' ' The S N 2 mechanism has been shown NT to take place in most esters by several kinds of experimental probes:

13 13 (1) Stereochemical studies: retention of configuration, not inversion, is observed in the hydrolysis of esters with a chiral center at the alkoxy carbon (S)-sec-butyl acetate (S)-sec-butyl ()-sec-butyl (2) 18 -Labeling studies: xygen-18 at the alkoxy oxygen is found to be retained by the alcohol, not the carboxylate NT 2 3 NT What is the evidence that a tetrahedral structure is involved as an intermediate, rather than only as a transition state? Why not substitution in a single step? δ ' ' δ ' This possibility was eliminated for saponification of esters by another 18 -labeling study, in which it was shown that isotopic exchange of acyl oxygen takes place in the unreacted portion of ester after partial hydrolysis: product ' 18 ' ' loss of label after partial reaction 18 ' symmetrical intermediate ' 18 ' 18 product 18 ' Such an exchange could not take place in the one-step reaction.

14 14 In the hydrolysis reactions, esters react with nucleophilic or, but they can react with other nucleophiles as well: Trans-esterification: eaction with alcohols " ' ' " or Na " ' The reaction is an equilibrium under both acidic or basic conditions, and is driven to completion by use of a large excess of the alcohol as solvent. If it is low-boiling, the alcohol product, ', may also be distilled out of the reaction mixture to complete the reaction. " " ' " ' The mechanisms for transesterification are essentially the same as those of the hydrolysis reactions, except for the absence of a final acid-base reaction under alkaline conditions, which renders the reaction reversible, and the alkoxide a catalyst rather than a reagent that is consumed: Ammonolysis: eaction with Ammonia ' N 3 ' or N2 '

15 AMIDES: We have already seen that amides are most commonly prepared by reaction of ammonia or 1 and 2 amines with acid chlorides or anhydrides. The chemical bonding structure of amides is important in the peptide linkage of proteins, which are essentially polyamides: The resonance shown is important in decreasing bond rotation mobility around the N bond, and N 3 3 favoring a planar geometry of the amide functional group. This is readily observable in the NM spectrum of N,Ndimethylformamide (DMF), in which methyls in two environments are evident. ydrolysis of Amides: Amides are less reactive towards water than any of the other derivatives we have examined, but they can be hydrolyzed to carboxylic acids under either acidic or basic conditions: Acidic hydrolysis: N N N 3 N 3 N 4 Note that unlike acid-catalyzed ester hydrolysis, this reaction is NT an equilibrium, because the ammonia is converted by the acid to the non-nucleophilic ammonium ion. This also results in consumption of acid, so the reaction is not truly acid-catalyzed.

16 16 Basic hydrolysis: N2 N 3 Just as saponification is not reversible, neither is this one--and for the same reason: the carboxylate ion is not subject to nucleophilic attack. eduction: As with all the other carboxylic acid derivatives, amides can be reduced by lithium aluminum hydride: Al 3 N ' " Example: The product in this example is a primary amine, but secondary and tertiary amines can also be synthesized in this way. This reaction is one of the important methods for synthesis of amines. Al 3 N'" LiAl LiAl N'" ' 2 N " 2 NITILES Preparation From Alkyl alides The cyanide anion is a strong nucleophile, and will react with primary alkyl halides to give the corresponding nitrile through an S N 2 substitution. 2 Br NaN -----> 2 N Because the cyanide ion is significantly basic, it will promote the E2 base-catalyzed dehydrohalogenation reaction with tertiary and many secondary alkyl halides, producing alkenes instead of the desired nitriles.

17 Dehydration of Amides Nitriles can also be prepared by dehydration of primary amides. Several reagents can accomplish this: Sl 2 N S 2 2 l N 2 or P N 2 3 P 4 This synthetic route to nitriles is particularly useful when the S N 2 reaction is not possible, i.e., with 3 alkyl or aryl halides. ( 3 ) 3 l BUT Mg/ether ( 3 ) 3 Mgl N 2 ( 3 ) 3 N 3 N 3 1. BrMg 2 5 ( 3 ) N 4 P Sl ( 3 ) ( 3 ) 3 2. N 3 eactions of Nitriles: ydrolysis N 2 or Mechanisms for hydrolysis: In Acid: N 3 N 2 2 N 2 In Base: N N N 2 N 2 2 N

18 18 eduction Nitriles can be reduced by lithium aluminum hydride to give primary amines, just as in the reduction of unsubstituted amides: 2 N 1. LiAl owever, reduction of nitriles by diisobutylaluminum hydride, DIBA ((i-bu) 2 Al) provides another route for the synthesis of aldehydes (i-bu) 2 Al N N 4 N 3 imine conjugate base eaction of Nitriles with Grignard eagents By a mechanism similar to the DIBA reduction, reaction of nitriles with Grignard reagents allows preparation of ketones: N 3 N MgBr N 4 MgBr imine conjugate base ydrolysis of Imines in Above Syntheses of Aldehydes and Ketones: N ' N 2 ' ' 2 ' N 3 N 3 ' ' ' ' N 4 ' = = aldehyde product ' = alkyl, aryl = ketone product