CHAPTER 17. CARBOXYLIC ACIDS

Carboxylic acids are a class of organic compounds which contain the carboxyl functional group. They are the most common class of acidic organic compounds.

q In rapidly writing structures, the carboxyl group is sometimes written as –CO₂H .

q The carboxyl functionality is a compound functional group, containing both a carbonyl functionality and a hydroxyl functionality. However, this compound functionality is very different from either an alcohol or a ketone.

q Because the carbonyl and hydroxyl groups are directly attached to one another, there is a strong resonance interaction between the two groups, which sharply modifies the properties of the compound functionality from that of either of the two component functionalities.

Nomenclature.

q The IUPAC approach to naming carboxylic acids (which we will primarily focus upon) consists essentially of naming the subject compound as an alkanoic acid having various substituents at various positions.

q The suffix –oic is added to a stem corresponding to the longest continuous chain of carbon atoms which contains the carboxyl group. The carboxyl carbon is automatically numbered as the first carbon of that parent chain. The stem consists of the name of the alkane containing the same number of carbon atoms, except that the terminal –e of the alkane is dropped (e.g., methane becomes methan-).

q The simplest carboxylic acid is methanoic acid, the next ethanoic acid, etc. Benzoic acid has a special, IUPAC-approved name, since aromatic carboxylic acids are not easily named by the standard system.

q Substituent names and positional locants, arranged alphabetically, are added as appropriate for the subject compound.

q In di- or polyfunctional molecules, the carboxyl function takes precedence over most other functional groups for nomenclature purposes. In the example shown below, the molecule is named as a carboxylic acid, rather than as an alcohol.

q Note that, since the carboxyl carbon atom is always numbered as carbon-1, a locant is not used for the carboxyl group.

POLARITY, SOLUBILITY, AND BOILING POINTS.

q The carboxyl group is considered to be a very highly polar functional group. It not only has a highly polar C=O bond, but also a highly polar –OH bond.

q The lower molecular weight members of the carboxylic acid family, especially methanoic (formic) and ethanoic (acetic) acids, are sufficiently polar as to be completely soluble in water. As solvents, they are considered to be polar solvents, but not quite as polar as water. Solvent polarity is often measured by the ability to dissolve salts or to provide solvation stabilization for ions.

q Higher molecular weight carboxylic acids, tend to have less water solubility because of the dominance of the non-polar part of the molecule, which is “hydrophobic”. They are therefore more organic-soluble.

q The carboxyl group has both an acidic and a basic site. The acidic site is the protonic end of the O-H bond, and the most basic site is the carbonyl oxygen atom. As such, the carboxyl group is both a hydrogen bond donor and a hydrogen bond acceptor. Consequently, the neat (pure) liquids are highly hydrogen bonded intermolecularly (i.e., between molecules) and therefore have especially high boiling points for their molecular weights.

RESONANCE STABILIZATION

q As noted above, the carboxyl group is a compound functionality in which a hydroxyl group (an electron donor via the unshared pair on oxygen) and a carbonyl group (an electron acceptor because of the carbocation character of the carbonyl carbon atom) are directly connected. The result is strong resonance stabilization of the carboxyl group via the interaction between these two groups.

ACIDITY.

In a previous chapter, the acidity of carboxylic acids was considered in detail. A brief review of a few of the essential points about carboxylic acid acidity is presented here.

q The pK_a’s of simple carboxylic acids, such as acetic acid, are typically about 5.

q A comparison with the acidity of another class of organic compounds containing the hydroxyl group, viz., alcohols is instructive. Simple alcohols, such as ethanol, have pK_a’s of about 16, fully 11 pK_a units less acidic than carboxylic acids, although in both cases it is an O-H bond which undergoes dissociation. Incidentally, 11 pK_a units corresponds to a free energy difference of ca. 15 kcal/mol.

q What is the reason for the much greater acidity of the OH protons of a carboxylic acid than those of an alcohol? Primarily the resonance stabilization of the conjugate base of a carboxylic acid, i.e., the carboxylate anion. Recall that there are two equivalent resonance structures for this anion, so that resonance stabilization is especially strong.

q In contrast, the conjugate base of an alcohol, an alkoxide anion, is not resonance stabilized at all, i.e., the negative charge is fully localized upon the oxygen atom.

q Preferentially stabilizing the right hand side of the equation, results in an equilibrium shift to the right side, and the formation of more hydronium ion.

q However, our argument has, to this point, neglected one important issue, viz., the resonance stabilization of the carboxylic acid itself. Since this stabilization relates to the reactant (left hand) side of the equation, it is a factor which should cause the equilibrium to shift to the left, that is, it should cause a decrease in acidity.

q We therefore have one factor, resonance stabilization of the conjugate base, which tends to increase acidity, and one factor, resonance stabilization of the reactant carboxylic acid, which tends to decrease acidity. Which factor is dominant?

q Experimentally, we can see that, by the large factor of 15 kcal/mol, the resonance stabilization of the anion dominates the resonance stabilization of the carboxylic acid. This is because the experimental result is that the acidity of the carboxylic acid is actually increased.

q Since the carboxylic acid itself is strongly resonance stabilized, we can see the the resonance stabilization of the carboxylate anion is very large indee, i.e., fully 15 kcal/mol greater than that of the carboxylic acid.

q Is this result predictable theoretically? Decidedly, yes. Simply recall that the two best resonance structures of the carboxylate anion are equivalent, and therefore provide a maximum resonance stabilization. In the case of the carboxylic acid, the resonance structures are non-equivalent. In particular, the other structures have charge separation, which is an energy-increasing factor.

BASICITY OF CARBOXYLIC ACIDS

q The carboxylic acid function, besides possessing an acidic proton, has two non-equivalent basic sites. These are the carbonyl oxygen and the alcohol type oxygen.

q While carboxylic acids are much more acidic than basic, these basic sites are important as hydrogen bond acceptor sites in the intermolecular hydrogen hydrogen bonding which gives rise to the relatively high boiling points of carboxylic acids.

q The basic oxygen sites, especially the carbonyl oxygen, are, however, accessible to protonation in acidic aqueous solution containing strong acids. In fact, these carbonyl oxygens are even more basic than those in ketones or aldehydes. This will prove to be important when we look at the diborane reductions of carboxylic acids further along.

q First: Why is the carbonyl oxygen more readily protonated than the ether type oxygen? Note that the carbonyl oxygen-protonated conjugate acid of a carboxylic acid is highly resonance stabilized (see below), while the alcohol oxygen-protonated conjugate acid is not.

q Further, the latter conjugate acid has a center of positive charge (the protonated alcohol oxygen) directly adjacent to the highly electron deficient carbonyl carbon, which has a large partial positive charge. The electrostatic repulsion between these two directly attached sites is therefore strongly destabilizing to the alcohol oxygen-protonated conjugate acid.

q Second: Why is the carbonyl oxygen of a carboxylic acid more readily protonated than the corresponding carbonyl oxygen of an aldehyde or ketone? Again, please note that the conjugate acid of a carbonyl compound lacks the third resonance structure which is significant in the stabilization of the conjugate acid of the carboxylic acid. Essentially, the conjugate acid of a ketone has partial positive charge on just two atoms, the carbonyl oxygen and the carbonyl carbon, while the conjugate acid of the carboxylic acid has the postive charge delocalized on three atoms. These are the carbonyl oxygen, the carbonyl carbon, and the alcohol type oxygen.

PREPARATION OF CARBOXYLIC ACIDS.

We have previously discussed two methods (at least) for preparing carboxylic acids. We want to briefly review these two methods.

The Oxidative Approach.

q In the chapter on the alcohol functional group, we saw that primary alcohols could be oxidized to aldehydes by aqueous chromic acid oxidation, but also that aldehydes, if not quickly removed from solution, would rather quickly be further oxidized to carboxylic acids.

q In employing the term “oxidation” in the context of organic reactions, it is important for us to remember that carbon is considered to exist in various possible oxidation states ranging from that present in alkanes (the zero oxidation state), to that in alcohols or ethers (the +1 oxidation state), to aldehydes and ketones (the +2 oxidation state), to carboxylic acids and esters (the +3 oxidation state), and finally to carbon dioxide (the +4 oxidation state). These oxidation states can be considered as reflecting the number of bonds to oxygen that a given carbon has and the fact the carbon is the positive end of the polar covalent bond, with oxygen being the negative end (in each case oxygen has the –2 oxidation state).

q Any conversion which increases the number of C-O bonds is considered an oxidation (any conversion which generates a product which is further to the right on this list). Any conversion which decreases the number of C-O bonds is considered a reduction.

q Consequently, the conversion of a primary alcohol to an aldehyde is considered an oxidation, as is the conversion of an aldehyde to a carboxylic acid.

q On the other hand, the conversion of a carboxylic acid to an aldehyde or an alcohol is considered to be a reduction.

q Oxidizing agents, i.e., agents which are able to bring about oxidation reactions, are often inorganic reagents containing atoms (especially metals) in a high oxidation state, which can be converted to a lower oxidation state. Thus, chromic acid, in which chromium has an oxidation state of +6, is an appropriate oxidant for the conversion of either a primary alcohol or an aldehyde to a carboxylic acid. In the process chromium is converted to the +3 oxidation state.

q The mechanisms of these reactions were considered in the first semester of this course and are not of further concern to us here. Please remember,however, that, unlike aldehydes, ketones are not easy to oxidize to carboxylic acids.

A Synthesis of Carboxylic Acids Which Involves Reduction.

q Only carbon dioxide contains carbon in a higher oxidation state that carboxylic acids. The reaction of Grignard reagents (nucleophilic reagents) with carbon dioxide generates carboxylate anions, which upon acidic aqueous workup yield carboxylic acids.

REACTIONS OF CARBOXYLIC ACIDS

q By far the most common reactions of carboxylic acids are deprotonation (that is dissociation of a proton) and protonation. Both of these have already been discussed rather extensively.

q Further oxidation of a carboxylic acid (which requires very strenuous thermal oxidation conditions) can only yield carbon dioxide. Consequently, most of the reactions of carboxylic acids either involve reduction to an aldehyde or an alcohol, or they are not red-ox reactions at all. For example, we have noted that carboxylic acids and esters are at the same oxidation level. The conversion of a carboxylic acid to an ester therefore does not involve either oxidation or reduction.

Reduction Reactions.

Catalytic reduction.

1. We know that various unsaturated functionalities can be reduced by dihydrogen in the presence of transition metal catalysts.

2. Alkenes, having the weakest pi bonds, are easiest to reduce.

3. Carbonyl groups and aromatic rings are also reducible, but under more strenuous conditions of temperature and pressure.

4. Carboxylic acids have a carbonyl pi bond and, further, they have additional resonance stabilization. Consequently, they are harder to reduce than either alkenes or aldehydes/ketones.

5. The sequence of ease of reducibility is alkenes > aldehydes, ketones>carboxylic acids, aromatics.

6. Therefore, an alkene or an aldehyde/ketone function can be reduced selectively in the presence of a carboxylic acid moiety, without affecting the latter.

An Example:

Metal Hydride Reductions

q The electrophilic carbonyl carbon of an aldehyde or ketone makes it reactive toward metal hydrides, which contain nucleophilic hydrogen.

q The same is true for a carboxylic acid, except the latter is more highly resonance stabilized than an aldehyde or ketone and therefore inherently less reactive than a carbonyl compound.

q There is an even more serious problem with the reduction of a carboxylic acid by a hydride such as lithium aluminum hydride, i.e., the acid is acidic and prefers to very quickly protonate the basic hydride reagent, giving dihydrogen and the carboxylate salt of the metal. The negatively charged carboxylate anion is highly resonance stabilized and reacts with only the most reactive hydride reagents and even so with some difficulty.

q Nevertheless, under these pressing conditions, carboxylic acids can be reduced to primary alcohols.

q IMPORTANT: Keep in mind that alkene pi bonds, which are not electrophilic, are not reduced by (nucleophilic) hydride reagents at all, so even carboxylic acid functionalities can be reduced selectively in the present of an alkene function.

Selective Reduction of the Carbonyl Function in the Presence of a Carbonyl Function: Borane Reductions

There is an especially clever strategy for the selective reduction of a carboxylic acid function even in the presence of an aldehyde or ketone function. Recall that this could not be accomplished with LAH or other metal hydrides, because the carboxylic acid function is resonance stabilized and therefore less reactive than a carbonyl function, and also because initial reaction of a hydride reagent with a carboxylic acid is an acid/base reaction which generates dihydrogen and the extremely unreactive, highly resonance-stabilized carboxylate anion. Strategies like this are important in organic synthesis in enabling one to direct reaction toward an inherently more stable, generally less reactive functionality.

q Note, first, that borane is not a metal hydride. Boron is not a metal, and the hydrogens of borane are not especially hydridic in character. Consequently, there is no Bronsted acid/base reaction which converts the carboxylic acid to a very unreactive carboxylate anion, as occurred in the case of LAH.

q Rather, borane is electrophilic, since the boron has a vacant 2p AO. The reaction between borane and a carboxylic acid is a Lewis acid/base reaction in which borane is the Lewis acid and the carboxylic acid (via the unshared pairs of the carbonyl oxygen: recall that this is the more basic oxygen) is the Lewis base.

q This reaction converts the neutral, electrophilic borane to a negatively charged hydride reagent, in which the hydrogens are now quite nucleophilic!

q Simultaneously, it converts the carboxylic acid to its (Lewis) conjugate acid (a postively charged, oxonium ion), which (like the corresponding Bronsted conjugate acid) has much more carbocation character at the carbonyl carbon. The activated hydride is then able to react very efficiently at this activated electrophilic center.

q In the product, which is analogous to the hydrate of a carbonyl compound, the former carboxyl carbon has been reduced to the +2 oxidation state, which is the same as that of a carbonyl compound. Loss of HOBH₂ generates the aldehyde.

q If conditions are controlled carefully, the aldehyde can be isolated in good yield. However, if desired, this can be reduced further with an excess of the borane to the alcohol. But remember, the carboxylic acid is more reactive than a carbonyl compound, so this reaction can be stopped at the aldehyde stage.

q Why is the carboxylic acid function, which is imore highly resonance stabilized than an aldehyde function, more reactive than the aldehyde function? Simply because the carboxylic acid is more basic. Recall the previous discussion of the basicity of carboxylic acids, which revealed that the conjugate acid of a carboxylic acid has the positive charge delocalized over three atoms, the carbonyl oxygen, the carbonyl carbon, and the alcohol-type oxygen. So borane preferentially forms the complex with the more basic carbonyl oxygen of the carboxylic acid.

ESTERIFICATION OF CARBOXYLIC ACIDS

Many reactions of carboxylic acids involve neither oxidation nor reduction. That is, the oxidation state of the carboxyl carbon remains at +3. The conversion of a carboxylic acid to a carboxylate ester is one such reaction.

q In an overall reaction sense, this is a substitution reaction, since the –OH group is replaced by an –OR’ group.

q The substitution reaction does not, however, occur via an S_N1 or an S_N2 mechanism. Rather, it occurs in a two stage mechanism involving, first, addition to the carbonyl group in a manner analogous to the addition of an alcohol to an aldehyde or ketone carbonyl group (hemiacetal formation), followed by an elimination reaction, in which water is eliminated from the previously formed adduct. Addition/elimination is a typical route for substitution processes in carboxylic acids, esters, amides, and other analgous acyl compounds in which carbon has the +3 oxidation state.

q The addition phase of the reaction is comprised of the first two steps. Essentially an acid-catalyzed addition of an alcohol to the carbonyl group of the carboxylic acid. The acid catalyst is shown as the conjugate acid of the alcohol, since in many cases these esterification (ester-making) reactions are carried out in the alcohol as a solvent. This is why methyl and ethyl esters are so common.

q The third step is just a proton transfer from the –OR’ group to an -OH’ group, so that water can be set up as a good leaving group.

q The fourth step is an S_N1-like reaction (with water as the leaving group) in which a carbocationic intermediate is generated, but the other two resonance structures (especially the second one) reveal that this is just the conjugate acid of the product ester. Removal of the proton from this in step 5 generates the ester and regenerates the catalyst. The last two steps constitute the elimination stage of the reaction.

q Note that the thermodynamic stabilities of the carboxylic acid and carboxylate ester functions are very similar, so that the equilibrium constant K is about 1. The use of a large excess of the alcohol as the solvent, however, can drive the equilibrium to completion.

q If the alcohol is not such that a large excess can be used, the equilibrium can be driven to the right by the removal of water (the LeChatelier principle) via distillation or the use of a dehydrating agent.

q The reason that these two functionalities are of such similar energy is that the resonance stabilization of both is about the same. Compare the three resonance structures below with the three written previously for the carboxylic acid function.

q It is important to note that a base-catalyzed mechanism for the esterification of a carboxylic acid does not exist. When one uses hydroxide anion as a base catalyst (or whatever other basic catalyst is used), the preferred reaction is not addition to the carbonyl group, but deprotonation of the carboxyl group to give the carboxylate conjugate base, which is highly unreactive because of both its resonance stabilization and its negative charge.

q In the next chapter we will see that the reverse reaction, the conversion of an ester to a carboxylic acid can be carried out in either acidic or basic solution.