TB4 Ch2 - Apuntes 4.2 PDF

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Organic chemistry Thematic block 4, Chapter 2 Carboxylic acids and derivatives Figures taken in part from: P. Y. Bruice, Organic Chemistry, 5th Ed., Pearson Prentice Hall Inc., 2007.

Nomenclature, electronic structure and physical properties of carboxylic acids

Nomenclature, electronic structure and physical properties of carboxylic acids In carboxylic acids, the carbonyl carbon shows electrophilic character. The two oxygen atoms are basic (Lewis) while the hydrogen atom displays acidic (Brønsted) character.

Nomenclature, electronic structure and physical properties of carboxylic acids The presence of the carboxyl function is denoted with the expression –oic acid after the root that indicates the number of carbon atoms in the main chain (the one containing the carboxyl function and other functions if present, always taking the order of precedence into account). Numbering of the chain starts with the carboxyl carbon, set to 1.

Nomenclature, electronic structure and physical properties of carboxylic acids The presence of the carboxyl function is denoted with the expression –oic acid after the root that indicates the number of carbon atoms in the main chain (that containing the carboxyl function and other functions if present, always taking the order of precedence into account). Numbering of the chain starts with the carboxyl carbon, set to 1.

Nomenclature, electronic structure and physical properties of carboxylic acids When two carboxyl groups are situated at the end of a chain, the multiplicative suffix –dioic (acid) is used.

Nomenclature, electronic structure and physical properties of carboxylic acids When the carboxyl group cannot be inserted into a carbon chain (for example, when bound to a ring) the substitutive suffix –oic cannot be used. In this case, the additive suffix –carboxylic acid must be used instead. CO2H 1 5

3

HO2C

CO2H

Benzene-1,3,5-tricarboxylic acid CO2H 1 2

OH

(1R,2R)-2-Hydroxycyclobutanecarboxylic acid

Nomenclature, electronic structure and physical properties of carboxylic acids

Nomenclature, electronic structure and physical properties of carboxylic acids Molecular shape of a simple acid: formic acid

Nomenclature, electronic structure and physical properties of carboxylic acids The carboxyl group is a strongly polar function due to the coexistence of a carbonyl (hydrogen-bond acceptor) and a hydroxyl group (hydrogen-bond donor). This feature causes the formation of cyclic dimers which explain the comparatively high boiling points. The high polarity is also the cause of the high water solubility.

Nomenclature, electronic structure and physical properties of carboxylic acids

Nomenclature, electronic structure and physical properties of carboxylic acids

Reactivity of the carboxyl group: nucleophilic substitution processes

Reactivity of the carboxyl group There is an important difference between aldehydes and ketones, on one hand, and carboxylic acids and their derivatives, on the other hand. The latter also exhibit the general formula RCOL but, in contrast to the former, the atom L is neither hydrogen nor carbon but an electronegative heteroatom (L = O, N, Hal, S, etc.) bearing one or more free electron pairs.

Reactivity of the carboxyl group  As in any carbonyl compound, carboxylic acids and their derivatives exhibit electrophilic reactivity in the C=O fragment, which is attacked by nucleophilic species Nu. The basic reactivity pathways therefore are essentially identical to those observed in aldehydes and ketones.  The main difference is how the intermediate species I (see below) evolves. In aldehydes and ketones intermediate I combines with an electrophilic species E+, usually a proton.  The overall result therefore is a nucleophilic addition to the carbonyl group.

Reactivity of the carboxyl group In carboxylic acids and derivatives, however, intermediate I is unstable because of the repulsion between the free electron pairs at L and those at the negatively charged oxygen atom. In consequence, the L fragment is expelled, and the carbonyl group is regenerated. The overall observed reaction therefore is a nucleophilic substitution resulting from an addition /elimination sequence.

Reactivity of the carboxyl group The aforementioned reaction may be also viewed as an acylation of the nucleophile. Thus, it will be the faster the better is L as a leaving group, i.e., the weaker is L as a base. Indeed, the worst acylating agents are carboxylic acids, because they also display the worst leaving group (OH). Moreover, strong nucleophiles are usually also strong bases. Thus, when they are allowed to react with carboxylic acids, the kinetically most favorable process will be proton transfer from the COOH group (acid-base reaction) with formation of an almost unreactive carboxylate anion.

Reactivity of the carboxyl group The aforementioned reaction may be also viewed as an acylation of the nucleophile. Thus, it will be the faster the better is L as a leaving group, i.e., the weaker is L as a base. Indeed, the worst acylating agents are carboxylic acids, because they also display the worst leaving group (OH). Moreover, strong nucleophiles are usually also strong bases. Thus, when they are allowed to react with carboxylic acids, the kinetically most favorable process will be proton transfer from the COOH group (acid-base reaction) with formation of an almost unreactive carboxylate anion.

Most nucleophiles

Reactivity of the carboxyl group In spite of this, the carboxyl OH may be replaced by a nucleophile under a few specific conditions. One example is the Fischer esterification, which takes place in an acidic medium.

The reaction is practically neutral from the thermodynamic point of view (Keq  1). Thus, in order to drive it to completion it is necessary to remove the water from the reaction medium or else to use an excess of one the reagents.

Reactivity of the carboxyl group For example, either the alcohol or the acid (the cheapest one) may be used as the solvent to guarantee the presence of an excess (in most cases, the alcohol is used for this purpose).

The generally accepted reaction mechanism is the following:

Reactivity of the carboxyl group

Reactivity of the carboxyl group This is not the only method to directly prepare esters from carboxylic acids. Another useful method is based on a SN2type reaction between a carboxylate anion RCOO and an alkyl halide R´X. Of course, this method is subjected to the usual limitations observed in SN2 reactions, i.e. it works well only with primary and unhindered secondary halides.

Irrespective of all this, the most usual method to prepare esters involves the use of reactive carboxylic acid derivatives (mainly acid halides). This topic will be treated later in this chapter.

Reactivity of the carboxyl group Very few strong nucleophiles are able to directly attack the carboxyl group. One of them is LiAlH4 (lithium aluminum hydride) which converts acids into primary alcohols. In contrast, sodium borohydride (NaBH4) is not able to reduce carboxylic acids.

Reactivity of the carboxyl group Since LiAlH4 is a very strong base, it reacts with the COOH group and causes an initial proton transfer. Gaseous H2 is then formed with generation of the very unreactive carboxylate anion. The nucleophilic reactivity of the hydride is so high that it is able to attack the carboxylate anion to give an intermediate aldehyde (complexed with the aluminum atom). A second hydride transfer to the latter finally yields, after acidic work-up of the reaction mixture, the primary alcohol.

Reactivity of the carboxyl group Other strong nucleophiles that are able to react with carboxylic acids are organolithium reagents, R´Li. After initial proton transfer to yield the carboxylate anion (lithium salt), the latter is attacked by a second molecule of the nucleophilic reagent to yield a geminal dialkoxide. Hydrolytic workup yields a geminal diol, rapidly converted into a ketone. Grignard reagents do not perform well in this reaction because the initially formed magnesium salt precipitates and does not react further.

Synthesis of carboxylic acids

Synthesis of carboxylic acids A number of organic reactions can be used for the preparation of carboxylic acids. The following ones deserve mention:  Oxidation of primary alcohols and aldehydes  Reaction of organolithium and organomagnesium derivatives with CO2  Hydrolysis of nitriles (to be treated in Chapter 3)

Oxidation of primary alcohols and aldehydes It has been commented in previous Chapters that many reagents are able to oxidise hydroxyl to carbonyl groups. Oxidants based on chromium(VI) compounds such as CrO3 or M2Cr2O7 (M = Na, K) can convert primary alcohols into aldehydes but do not stop at this phase and further oxidise the latter rapidly to carboxylic acids. Obviously, the same and many other reagents can oxidise aldehydes to carboxylic acids.

Reaction of organometallics with CO2 Organometallics based on lithium and magnesium react with CO2, a weak electrophile, to yield carboxylate anions. Acidic work-up of the reaction mixture affords the carboxylic acid.

Reactivity of the carbonyl group in carboxylic acid derivatives: nucleophilic substitutions via addition/elimination pathways

Reactivity of the carbonyl group in carboxylic acid derivatives Remember now what we have said previously in this Chapter: (“…in carboxylic acids and derivatives, however, intermediate I is unstable because of the repulsion between the free electron pairs at L and those at the negatively charged oxygen atom. In consequence, the L fragment is expelled, and the carbonyl group is reformed...”) The overall observed reaction therefore is a nucleophilic substitution resulting from an addition/elimination sequence.

Reactivity of the carbonyl group in carboxylic acid derivatives Remember now what we have said previously in this Chapter: The aforementioned reaction may be also viewed as an acylation of the nucleophile. Thus, it will be the faster the better is L as a leaving group, i.e., the weaker is L as a base. Indeed, the worst acylating agents are carboxylic acids, because they display the worst leaving group (OH). Furthermore, strong nucleophiles are usually also strong bases. Thus, when they are allowed to react with carboxylic acids, the kinetically most favorable process will be proton transfer from the COOH group (acid-base reaction) with formation of a highly unreactive carboxylate anion.

Most nucleophiles

Reactivity of the carbonyl group in carboxylic acid derivatives

In general terms, all carboxylic acid derivatives RCOL (acyl halides, anhydrides, esters and amides) follow in their reactions the aforementioned nucleophilic substitution mechanism via an addition /elimimination sequence through the intermediate species I.

Reactivity of the carbonyl group in carboxylic acid derivatives

This general statement about the mechanistic pathways is true for all carboxylic acid derivatives. However, these show very marked differences in their reaction rates. The experimentally observed order is: halides > anhydrides >> esters >> amides

Reactivity of the carbonyl group in carboxylic acid derivatives

Reactivity of the carbonyl group in carboxylic acid derivatives In general terms, the factors that have an influence in the reactivity of carboxylic acid derivatives towards nucleophiles are of three types:  The electronegativity of L: a high value involves a decrease of the electron density at the carbonyl carbon, i.e. an increase in the electrophilicity. This factor has its maximum value with halogens and its minimum value with nitrogen.  The ability of L as a leaving group, related in turn with the polarizability of the C L bond, and also with the acidic strength of HL. As above, this factor has its maximum value with halogens and its minimum value with nitrogen.  The mesomeric donor ability of L:, which reflects in the bond order and therefore the strength of the CO L bond. This factor has its maximum value with nitrogen and its minimum value with halogens.

C L bond strength: N > O > Hal

Reactivity of the carbonyl group in carboxylic acid derivatives The reaction kinetics is controlled by the magnitude of the process activation barrier. Any factor that stabilizes (destabilizes) the transition state (TS) in comparison with the initial state, will accelerate (slow down) the process. Because of the higher degree of mesomeric interaction in amides, the initial state is more stabilized in them in relation to the TS in halides. This explains the higher reactivity of the latter.

maximum stabilization in amides minimum stabilization in halides

Reactivity of the carbonyl group in carboxylic acid derivatives

Halides Difference in energy barrier

Amides

Highest reactivity in acyl halides, lowest in amides, intermediate values in anhydrides and esters.

Reactivity of the carbonyl group in carboxylic acid derivatives

The high electronegativity and leaving group ability of L favor reactivity in the case of halides. The low mesomeric donor ability of L also favors reactivity of halides. Thus, taking into account the combined influence of all these factors, it is easy to understand why acyl halides exhibit the highest reactivity and amides the lowest one among carboxylic acid derivatives.

halides > anhydrides >> esters >> amides

Acyl halides

Acyl halides They are named according to the corresponding carboxylic acid with replacement of alkanoic acid by alkanoyl halide. In acids where the name requires the use of the additive suffix –carboxylic acid, the latter will be replaced by –carbonyl halide.

Acyl halides Preparation

Acyl halides are prepared using the same reagents as for the conversion of alcohols into halides. However, only chlorides and, in very few cases, bromides are prepared in practice. Acyl fluorides and iodides are rarely used.

Acyl halides Acyl halides react with water (in some cases violently) to give the corresponding acids and with alcohols to yield esters. An equivalent amount of a base is added in order to neutralize the acid (HalH) formed. These processes follow the known addition-elimination sequence.

Acyl halides Acyl halides react with amines to yield amides. The process also follows the addition-elimination sequence.

Acyl halides Acyl halides can also react with carbon nucleophiles through the same addition-elimination sequence. In the case of organometallics, two equivalents of the reagent are consumed. The first step affords a ketone which, under these conditions, further reacts to yield a tertiary alcohol with two identical residues. The first reaction is faster than the second but, for organolithium and for organomagnesium reagents, the difference in reaction rates is in most cases not high enough to permit stopping the process after the first step with formation of a ketone.

Acyl halides Additional strong nucleophiles that react well with acyl halides are hydride reducing agents such as NaBH4 and LiAlH4. The first reduction step generates the corresponding aldehyde but the latter is also readily reduced under the same conditions to the primary alcohol.

Acid anhydrides

Acid anhydrides They are named as the corresponding acid with the word acid replaced by anhydride. Their chemical properties and reactivity are similar to those of acyl halides. However, they are much less frequently used than the latter because in their reactions half of the carbon atoms are wasted. Only some simple, commercially available anhydrides (acetic anhydride in most cases) are employed.

Acid anhydrides Some dicarboxylic acids can be dehydrated to cyclic anhydrides by means of heating at an elevated temperature. However, this happens only with diacids in which the two carboxyl groups are separated by a two- or three-carbon chain, because five- or six-membered rings are formed in these particular cases.

Acid anhydrides Among the acid derivatives RCOL with L being oxygen, anhydrides (RCO)2O are much more reactive (carbonyl group much more electrophilic) than esters (RCOOR´) because the electron pairs at the central oxygen atom in anhydrides are shared by two carbonyl groups. For that reason the mesomeric stabilization degree achieved in anhydrides is lower than in esters.

Acid anhydrides Anhydrides undergo similar reactions to those observed in acyl halides. However, these reactions are somewhat slower and accompanied by loss of half of the carbon atoms. Cyclic anhydrides give the same reactions as acyclic ones but without loss of carbon atoms.

Esters

Esters They are named as alkyl alkanoates, where this means a combination of the alkanoic acid and the alcohol (alkyl) from which they are formally derived. When a –CO2R group is a substituent of a larger structure, it has to be named as an alkoxycarbonyl group (for example, –CO2CH3 is a methoxycarbonyl group).

Esters As acylating agents, esters are not very reactive and occupy the third place in the sequence of electrophilic reactivity after halides and anhydrides. One of the reactions in which esters work efficiently is hydrolysis, which may be carried out in an either acidic or basic medium. The reaction below is an example of ester hydrolysis in an acidic medium.

Like the reverse process (Fischer esterification), acid hydrolysis is an equilibrium, with the acid acting as a catalyst. Thus, the reaction is favored by an excess of water and will always be performed either in water or in a solvent containing water. The mechanism is the same of the Fischer esterification even though in the opposite sense.

Esters Ester hydrolyses performed in a basic medium receive the name saponifications (from the Latin word sapo, soap). In this case, however, the base is not a catalyst because the process requires a full equivalent of the base (OH).

Esters Ester hydrolyses performed in a basic medium receive the name saponifications (from the Latin word sapo, soap). In this case, however, the base is not a catalyst because the process requires a full equivalent of the base (OH). The word saponification comes from the fact that basic hydrolysis of esters of glicerine (present in natural fats) has been the basis for soap preparation.

Esters One of the few heteroatomic nucleophiles which can be efficiently acylated by esters are amines. The reaction of esters with amines is relatively slow but gives amides with acceptable yields.

Esters When a carboxyl and an alcohol function coexist in the same molecule, an internal (intramolecular) esterification is possible. The result is a cyclic ester called a lactone. This process (lactonization) takes place in a spontaneous way when it gives rise either to a five-membered ring (-lactone) or else to a sixmembered ring ( -lactone).

Esters Esters also react with carbon nucleophiles, for example, lithium and magnesium organometallics (two equivalents). The reaction mechanism is the same as that observed with acyl halides. As for the latter, the ketone formed after the first step further reacts with the second equivalent of reagent to yield a tertiary alcohol with two identical residues. In contrast to acyl halides, the first reaction is now slower than the second, and the resulting ketone is more reactive than the starting ester. For that reason it is not possible to stop the process after the first step to obtain a ketone.

Esters Esters also react with carbon nucleophiles, for example, ...