Chem 263 Nov 26, 2013 Carboxylic Acids and Derivatives Nomenclature – Esters Systematic names for esters are derived by first giving the name of the alkyl group attached to the oxygen, and then identifying the carboxylic acid portion of the molecule. In doing so, the “-ic acid” is replaced with “-ate”. When naming, the C1 carbon is always the carbon attached to the oxygen in the alkyl chain and the carbonyl in the acid portion.

R

O

O R'

alkylacid

In the below example, the alkyl chain is identified as an ethyl group and the carboxylic acid is identified as acetic acid. Identification of the alkyl chain and dropping the “-ic acid”, replacing it with “-ate”, gives the name ethyl acetate. The systematic name for this compound would be ethyl ethanoate.

O

O

ethylacetic acid

ethyl acetate ethyl ethanoate Amide Name the corresponding acid, drop “-ic acid” or “oic acid”, add “amide”. If there is alkyl group on the amide nitrogen, then precede the chemical name with N-alkyl, such as N-methyl. Classification:

R1C

NH

H

O

Primary amide where there are two hydrogens attached to amide nitrogen If R1=H Formamide

methanamide

R1C

NR

H

O

Secondary amide where there is one hydrogen attached to amide nitrogen

If R1=H N-methylformamide

R1C

NR

R

O

Tertiary amide where there is no hydrogen attached to amide nitrogen If R1=H dimethylformamide

Usually amides are planar, because the lone pair on nitrogen can conjugate into the carbonyl.

R1C

NH2

O

R1C

NH2

O

Example:

HC

NH2

O

Nomenclature: Formamide. The corresponding parent acid is formic acid. Follow the rule above, drop “ic acid” and replace with “amide”, the above molecule is named as formamide. Systematically, it is known as methanamide. Example:

HC

NH

O

H2C

CH3 Nomenclature: N-ethylformamide. The letter “N” at the beginning of the name indicates that the ethyl group is attached on the nitrogen. Example:

HC

N

O

CH3

CH3 Nomenclature: N, N-dimethylformamide (DMF). This is a very common polar aprotic solvent. Make sure you know its name and structure. It may also be named N,N-dimethylmethanamide. Carboxylate Salts The general form of a carboxylate salt is:

R O

O

M where M is usually a metal ion. Carboxylate salts are named by first specifying the cation (such as sodium or ammonium), and then naming the carboxylic acid, where the “ic acid” is replaced with “ate.” Example:

O

O

Na

O

O NH4

This counterion in this molecule is sodium, so we include it first. The carboxylic acid is acetic acid, so we replace the “ic acid” with “ate” and get acetate. Therefore, this molecule is known as sodium acetate. Examples:

O

O

NH4 O

O

Na

Ammonium benzoate Sodium benzoate Ammonium acetate Nomenclature examples: Example:

COOH

Arachidonic Acid Arachidonic acid is a polyunsaturated fatty acid, and is one of the essential fatty acids required by most mammals. It is a precursor in the production of eicosanoids: the prostaglandins, thromboxanes, prostacyclin and the leukotrienes (through enzymes including cyclooxygenase, lipoxygenase and peroxidase). Chemically, arachidonic acid is a carboxylic acid with a 20-carbon chain and four cis double bonds. Recall from previous lecture, a 20-carbon alkane is named eicosane. To name the acid, you would drop ‘-e”, add “oic acid”. Since arachidonic acid has 4 double bonds, it would an eicosatetraene. All double bonds are cis, therefore are in Z configuration. Putting everything together, the systematic name is 5Z,8Z,11Z,14Z-eicosatetraenoic acid. Example:

NH2

O

The molecule shown is a sleep hormone Oleamide. It has 18 carbons. An 18 carbon alkane is called octadecane. The corresponding alkene would be octadecene. The corresponding acid would be 9-octadecenoic acid, and for the amide the systematic name is 9Z-octadecenamide.

Example: Below is an example of a molecule with two carboxylic acid groups. The first step to naming this compound is to find the parent alkane chain. Since it is a 6 carbon chain, it is a hexane. We then drop the “-e” and add “-oic acid” for the name to become hexanoic acid. Since there are two carboxylic acids present, the name becomes hexandioic acid. We notice that there is a double bond present in the molecule and therefore the name becomes hexendioic acid. The numbering of the chain should give the lowest number for the alkene, therefore the alkene is at C2 if you start numbering from the left, giving the name 2-hexendioic acid. Since the alkene is a trans double bond, the final name of this compound is 2E-hexendioic acid.

HO2CCO2H

1 3 5

2E-hexendioic acid

Another naming example is given below. The first step is to find the parent alkane chain. This example once again has a 6 carbon chain and is a hexane. We then drop the “-e” and add “-oic acid” for the name to become hexanoic acid. There are two double bonds present in the molecule and therefore the name becomes hexadienoic acid. The numbering of the chain gives the carboxylic acid carbon C1 and therefore the alkenes are at C2 and C4 if you start numbering from the left giving the name 2,4-hexadienoic acid. Both alkenes are trans double bonds, therefore the final name for this molecule is 2E,4E-hexadienoic acid.

HO2C1 3 5

2E,4E-hexadienoic acid

Example:

O

O

The molecule shown is a sex pheromone for elephants. What kind of functional groups are present in this molecule?

O

Oalkene ester

Recall for esters, you name the alkyl part first (drop “e” and add “yl”) and then the “ic acid” of the parent acid is replaced with “ate”. The alkyl group attached to oxygen has 12 carbons. A 12 carbon alkane is named a dodecane, and the corresponding alkene would be dodecene. The parent acid is acetic acid. When replaced with “-ate”, it is acetate.

O

O

1

2

3

4

5

6

78

9

10

11

12

dodecenyl acetate The systematic name for this pheromone is 7Z-dodecenyl acetate. If any part of this molecule is changed (remove a carbon, or extend by a carbon on the acetate part, or change the configuration of the double bond), it would not work as sex pheromone. Examples A more difficult example is the following growth inhibitor of fleas used in anti-flea powders on dogs and cats. When naming this compound, first the alkyl chain should be identified. The longest chain is 2 carbons and therefore is a substituted ethyl group. When numbering from the carbon attached to the oxygen, the methyl substituent is at C1 giving a 1-methylethyl (or isopropyl) chain. The acid portion of this molecule is a little more difficult. Firstly, we should identify the longest chain in the acid portion to get the parent alkane name. Since the longest chain is 12 carbons, it is a dodecane. Secondly, there are two trans alkenes in this molecule at the C2 and C4 positions when numbering starts at the carbonyl carbon to give dodeca-2E,4E-diene. The parent name for the acid would then be dodeca-2E,4E-dienoic acid. Since the molecule is an ester, dropping the “-ic acid” and replacing it with “-ate” gives the name dodeca-2E,4E-dienoate. Lastly is the naming of the substituents on the parent acid chain. At positions C3, C7, and C11 are methyl groups and at C11 is a methoxy group. The C7 methyl group is a stereogenic center and is in the S configuration. By combining the acid portion of the name and the alkyl portion, the final name for this molecule is isopropyl 11-methoxy-3,7S,11-trimethyldodeca-2E,4E-dienoate. Instead of isopropyl, one can call the alkyl part 1-methylethyl.

growth inhibitor of fleas used in anti-flea powder

Lactones: cyclic esters The ring size of the lactone can be described by starting at the carbonyl carbon and designating the other carbons in the ring with Greek letters (shown in figure) until the oxygen atom is reached.

O O O O

O O

O

O

!-lactone "-lactone#-lactone$-lactone

$

!

# "

!

!!$ $#

You should be able to recognize all four lactones shown above and know that lactones are cyclic esters. Example:

O O

bovolide Bovolide is responsible for the butter flavor. What kind of lactone is the above molecule? Answer: It is a γ-lactone. Specifically, an α,β-unsaturated γ-lactone.

O

O

CH3O

14681012

isopropyl 11-methoxy-3,7S,11-trimethyldodeca-2E,4E-dienoate

Example:

O

O

OH

OH

H

H

H

glycoside

This molecule is digitoxin from plant foxglove. It is a very toxic substance. In small amounts, it is a cardioactive drug. If taken in excess, it is a heart stimulant that can give instant heart attack. Is the O at position 3 on the A ring α or β substituted? Answer: it is β. What kind of lactone does it have? Answer: it is γ-lactone, since the lactone is 5-member ring. Lactams: cyclic amides Similar to lactones, the ring size of the lactam is described by starting at the carbonyl carbon and designating the other carbons in the ring with Greek letters until the nitrogen atom is reached. HN NH H

NHN

O O

O

O

!-lactam "-lactam#-lactam$-lactam The four-, five-, and six-member rings appear frequently in nature. Examples:

Properties of Carboxylic Acids Since carboxylic acids are structurally related to both ketones and aldehydes, we would expect to see some similar structural properties. The carbonyl carbon of carboxylic acids is sp2 hybridized with an approximate bond angle of 120°. The electronegative oxygen also makes the carbonyl carbon partially positively charged and susceptible to nucleophilic attack. Carboxylic acids with more than six carbons are only slightly soluble in water, but alkali metal salts of carboxylic acids are often quite water soluble because of their ionic nature. Other carboxylic acid derivatives, such as acid chlorides, anhydrides, and esters, are quite insoluble in water. Acid chlorides and anhydrides react with water, as we will see later. Some amide derivatives are also soluble in water. Like alcohols, carboxylic acids are strongly associated because of hydrogen bonding. Most carboxylic acids can exist as cyclic dimers held together by two hydrogen bonds, which are represented by the dashed lines.

RO

OR

O

OH

H

cyclic dimer

This strong hydrogen bonding has a noticeable effect on boiling points, making carboxylic acids much higher boiling than the corresponding alcohols >100°.

N

SHN

OCO2H

H

O N

SH2N

OCO2H

H

penicillin G 6-aminopenicillanic acid

Dissociation of Carboxylic Acids As the name implies, carboxylic acids are acidic. They therefore react with bases such as sodium hydroxide to give metal carboxylate salts. Like other Bronsted-Lowry acids discussed in previous courses, carboxylic acids dissociate slightly in dilute aqueous solution to give H3O+ (H+ + H2O) and carboxylate anions, RCOO-. The carboxylate anion is stabilized by resonance where the negative charge is delocalized over both oxygen atoms. Remember that we use a double-headed arrow only when electrons are being moved (resonance forms) and not when atoms are moving.

R

O

O H H2OR

O

O R O

OH+ H+

As with all acids, we can define an acidity constant Ka which equals the concentration of the carboxylate salt multiplied by the concentration of (H+) divided by the concentration of the carboxylic acid. Ka = [RCOO-] [H+] [RCOOH] For most carboxylic acids, Ka is approximately 10-5. Acetic acid, for example, has Ka = 10-4.5, which corresponds to a pKa of 4.5 (pKa = -log Ka). In practical terms, Ka values near 10-5 mean that only about one part in 100,000 is dissociated, as opposed to 100% dissociation found with strong mineral acids such as HCl and H2SO4. Substituent Effects on Acidity The pKa value of a carboxylic acid is quite different when it is substituted. Since the dissociation of a carboxylic acid is an equilibrium reaction, any factor that stabilizes the carboxylate anion relative to the undissociated carboxylic acid will drive the equilibrium toward increased dissociation and result in increased acidity. For example, an electron-withdrawing group attached to the carboxyl should inductively withdraw electron density, thereby stabilizing the carboxylate anion and increase acidity. An electron-donating group would conversely do the opposite.

Electronegative substituents, such as halogens, make the carboxylate anion more stable by inductively withdrawing electrons. Fluoroacetic acid and trifluoroacetic acid are both stronger acids than acetic acid because they stabilize the carboxylate anion by inductively withdrawing electron density.

O

OH FH2C

O

OH F3C

O

OH

pKa = 4.5 pKa = 2.6 pKa = 0.2 Preparation of Carboxylic Acids You have already seen most of the methods for the preparation of carboxylic acids so here is a review. Oxidative cleavage of an alkene with aqueous KMnO4 gives a carboxylic acid if the alkene has at least one vinylic hydrogen.

R

HR

H

KMnO4 RO

OR

O

OH

HheatH2O

KMnO4

Cold R

OHHO

R

Oxidation of an alkylbenzene derivative with KMnO4 gives a substituted benzoic acid derivative. Both primary and secondary alkyl groups can be oxidized but tertiary groups cannot.

H

RR' KMnO4

heatH2O

O

OH

Oxidation of primary alcohols and aldehydes yields carboxylic acids when oxidized with KMnO4 H2CrO4 or Jones reagent (CrO3, H2O, H2SO4). The oxidation of primary alcohols proceeds via an aldehyde intermediate, which is further oxidized to the carboxylic acid.

R OHH

H

KMnO4

or Jones reagent

H2CrO4

R

O

H R

O

O H

The haloform reaction converts a methyl ketone into a carboxylate salt plus a haloform (chloroform, CHCl3; bromoform, CHBr3; or iodoform, CHI3) and is the qualitative test for methyl ketones.

R CH3

O X2

NaOH R CX3

O NaOH

H2O R O- Na+

O+ CHX3

From alkyl halide (or Grignard reagent) and CO2: Example: Reactions of Carboxylic Acids and Derivatives: Strong Nucleophiles The strong nucleophiles (Nu: -) that we have learned in this course are either hydride anion (H-) or alkyl anion (R-). As well, remember that attack by strong nucleophiles is not reversible.

RO

OMgXRX RMgX

MgR

O

OH

H2O

HCl

CO2

R:OCO

Mg H2O

HCl

CO2Br MgBr CO2H

Hydride anion comes from hydride donor such as LiAlH4 or NaBH4 (however, NaBH4 is not strong enough reaction on carboxylic acid derivatives except for acid chlorides). Alkyl anion comes from RM, where R is an alkyl group and M is a metal (these reagents include Grignard reagents (RMgX) and alkyl lithium reagents RLi). Grignard reagents fail with carboxylic acids, but alkyl lithium reagents can be used. General mechanism:

R

O

Y

Nu

R

O

YNu

R

O

Nu

Nu

R

O

NuNuH

R

OH

NuNu

Addition of nucleophile depends on stability of leaving group. You can easily transform the most reactive carboxylic acid derivatives to less reactive carboxylic acid derivatives but you cannot easily transform the least reactive derivative to the most reactive derivative.

O

R Cl

O

R O

O

R

O

R O R

O

R N R

R

Most reactive toward Nuc

Least reactive toward Nuc

This step is reversible with weak nucleophiles but irreversible with strong

nucleophiles