Organic Chemistry Carboxylic Acid Derivatives

Question 1

Carboxylic acids can be converted into several types of \_\_\_: acyl halides, anhydrides, amides, and esters. These are compounds in which the -OH of the carboxyl group has been replaced with -X, -OCOR, -NH2, or -OR, respectively:
Acyl halide: R-CO-X
Anhydride: R-CO-O-CO-R
Ester: R-CO-OR'
Amide: R-CO-NH2 or R-CO-NR2

Answer 1

derivatives

Question 2

___ derivatives all have the highly polarized C||O group in which the carbon carries a partial positive charge and the oxygen has a partial negative charge. As a result, these compounds readily undergo nucleophilic substitution reactions, including hydrolysis (with H2O as the nucleophile). They also undergo other additions and substitutions, including various interconversions between different acid derivatives. In general, the acyl halides are the most reactive of the carboxylic acid derivatives, followed by the anhydrides, the esters, and the amides

Answer 2

carboxylic acid

Question 3

Each of these types of ___ will be discussed in turn. Although the variety of reaction pathways can appear overwhelming, they are all closely interwoven and should be studied in relation to each other.

Answer 3

carboxylic derivatives

Question 4

Acyl halides are also called acid or ___. The acyl group is written RCO-, and with the halide attached it is written as RCOX. Acyl halides are the most reactive of the carboxylic acid derivatives. They are named in the IUPAC system by changing the -ic acid ending of the carboxylic acid to -yl halide. Some typical examples are ethanoyl chloride (also called acetyl chloride), benzoyl chloride, and n-butanoyl bromide

Answer 4

alkanoyl halides

Question 5

Because the -OH of the ___ has been replaced by a halogen, an acyl halide is not able to form hydrogen bonds, acyl halides are therefore less polar than comparable carboxylic acids, and demonstrate significantly lower melting and boiling points

Answer 5

carboxyl group

Question 6

The most common acyl halides are the ___, although acid bromides and iodides are occasionally encountered. Acyl chlorides are prepared by reaction of a carboxylic acid with thionyl chloride, SOCl2, producing SO2 and HCl as side products, Alternatively, PCl3 or PCl5 (or PBr3, to make an acid bromide) can be used for this synthesis

Answer 6

acid chlorides

Question 7

Acyl halides are very reactive, as the greater electron-withdrawing power of the ___ makes the carbonyl carbon more susceptible to nucleophilic attack than the carbonyl carbon of a carboxylic acid. Because halides are excellent leaving groups, nucleophilic attack will always be followed by re-formation of the carbonyl. As a result, acyl halides readily undergo nucleophilic substitution reactions, including hydrolysis (with H2O as the nucleophile), which produces the original carboxylic acid. Acyl halides are also frequency used as intermediates in the conversion of carboxylic acids to anhydrides, esters, and amides

Answer 7

halogen

Question 8

The ___ of acid halides is their conversion back to carboxylic acids by classic nucleophilic attack. Acyl halides react very rapidly with water to form the corresponding acid, along with HCl, which is responsible for their irritating odor

Answer 8

simplest reaction

Question 9

Reaction of an ___ with a carboxylate salt will produce an anhydride through nucleophilic attack and re-formation of the carbonyl

Answer 9

acyl chloride

Question 10

Acyl halides can be converted into ___ by reaction with alcohols, The same type of nucleophilic attack found in hydrolysis leads to the formation of a tetrahedral intermediate, with the hydroxyl oxygen of the alcohol acting as the nucleophile. Chloride is displaced as the carbonyl re-forms, and HCl is released as a side product

Answer 10

esters

Question 11

Acyl halides can be converted into ___ (compounds of the general formula RCONR2) by nucleophilic substitution with amines. An amine, such as ammonia, attacks the carbonyl group, displacing chloride. The side product is ammonium chloride, formed from excess ammonia and HCl. Primary and secondary amines can also be used as the nucleophile to create N-substituted amides

Answer 11

amides

Question 12

___ can be acylated in a Friedel-Crafts reaction. The mechanism is electrophilic aromatic substitution, and the attacking reagent is an acylium ion, formed by reaction of an acid chloride with AlCl3, or another Lewis acid. The product is an alkyl aryl ketone

Answer 12

aromatic rings

Question 13

___ can be reduced to alcohols with a strong reducing agent such as LAH. They can also be selectively reduced to the intermediate aldehydes by catalytic hydrogenation in the presence of a “poison” such as quinoline, also called Lindlar’s catalyst

Answer 13

Acid halides

Question 14

Anhydrides, also called ___, are the condensation dimers of carboxylic acids, with the general formula RCOOCOR. They are named by substituting the word anhydride for the word acid in a carboxylic acid. Most anhydrides are symmetrical, although asymmetrical anhydrides exist and can be important in biological systems. The most common and important anhydride is acetic anhydride, the dimer of acetic acid. Other common anhydrides, such as succinic, maleic, and phthalic anhydrides are cyclic anhydrides arising from intramolecular condensation or dehydration of diacids

Answer 14

acid anhydrides

Question 15

Since ___ no longer have an -OH group, they do not have the ability to form hydrogen bonds. Anhydrides therefore are less polar and demonstrate lower melting and boiling points than comparable carboxylic acids of the same molecular weight (MW).

Answer 15

anhydrides

Question 16

Because anhydrides are often formed from the ___ of two other molecules, the product will have a higher melting or boiling point due to its larger size compared to the starting materials

Answer 16

condensation

Question 17

Although anhydrides are ___, they are not considered to be soluble in water because they immediately decompose in aqueous conditions to form carboxylic acids

Answer 17

polar

Question 18

The ___ pathways of anhydrides all involve some form of nucleophilic attack on a carboxylic acid, followed by the release of a leaving group and re-formation of the carbonyl

Answer 18

synthesis

Question 19

___ can be readily synthesized by reaction of an acyl chloride with carboxylate salt. This is the most efficient and most commonly used method of anhydride synthesis

Answer 19

anhydrides

Question 20

Certain cyclic anhydrides can be formed simply by heating ___. The reaction is driven by the increased stability of the newly formed ring; hence, only five- and six-membered ring anhydrides are easily made. In this case, the hydroxyl of one -COOH group acts as a nucleophile, attacking the carbonyl on the other -COOH group and releasing water

Answer 20

carboxylic acids

Question 21

Two ___ molecules can condense to form an anhydride in a reaction releasing water; however, this reaction requires anhydrous conditions. Therefore a dehydrating reagent that will remove the water produced in the reaction is needed to prevent immediate conversion back to the carboxylic acids. Reagents such as acetic anhydride, trifluoroacetic anhydride, phosphorous pentachloride, or dicyclohexylcarbodiimide (DCC) can be used for this purpose.

Answer 21

carboxylic acid

Question 22

___ react under the same conditions as acid chlorides, but since anhydrides are somewhat more stable, they are less reactive. Nucleophilic attack on an anhydride is slower and produces a carboxylic acid as the side product instead of HCl. Cyclic anhydrides are also subject to these reactions, which cause ring opening at the anhydride group along with formation of the new functional group

Answer 22

anhydrides

Question 23

Anhydrides are converted into carboxylic acids when exposed to ___. Note that in this reaction, the leaving group is actually a carboxylic acid; because the anhydride is symmetrical, it produces two molecules of the same carboxylic acid

Answer 23

water

Question 24

Anhydrides are cleaved by ___, producing an amide and a carboxylic acid. The carboxylic acid then further reacts with ammonia to form an ammonium carboxylate

Answer 24

ammonia

Question 25

___ react with alcohols to form esters; a single anhydride molecule will produce one ester and also one molecule of carboxylic acid

Answer 25

anhydrides

Question 26

Friedel-Crafts acylation occurs readily with anhydrides in the presence of AlCl3 or other ___. This reaction produces an aryl ketone and a carboxylic acid

Answer 26

lewis acid catalysts

Question 27

Esters are the dehydration products of carboxylic acids and alcohols. They are named in the IUPAC system as alkyl and aryl alkanoates. The alkyl chain attached to the non-carbonyl oxygen is named as a functional group; the carboxylic acid suffix -oic acid is replaced by -oate while retaining the carbon chain from the acid. ___, derived from the condensation of acetic acid and propanol, has the structure CH3COO-CH2CH2CH3 and is called propyl ethanoate according to IUPAC nomenclature

Answer 27

propyl acetate

Question 28

Since ___ do not have an -OH group, they do not have the same ability to form hydrogen bonds. Esters, therefore, are less polar and demonstrate lower melting and boiling points than comparable carboxylic acids of the same size. The water solubility of esters depends on the length of the hydrocarbon chain on the ester oxygen. Smaller esters have good water solubility, but as the chain becomes longer, water solubility decreases. This becomes important for very long chain esters that make up fats and oils

Answer 28

ester

Question 29

Esters can be readily obtained from the reaction of ___ with alcohols under anhydrous conditions. Phenolic (aromatic) esters are produced in the same way, although the aromatic acid chlorides are less reactive than aliphatic acid chlorides, requiring base to be added as a catalyst

Answer 29

acid chlorides

Question 30

Anhydrides react with alcohols to form esters,; a single anhydride molecule will produce one ester and also one molecule of ___ acid

Answer 30

carboxylic

Question 31

___ of carboxylic acids and alcohols will condense into esters under anhydrous conditions, liberating water. Use of sulfuric acid as a catalyst and a dehydrating reagent will drive the reaction forward

Answer 31

mixtures

Question 32

Esters react with ___ at the carbonyl carbon, although they are less reactive than acyl halides or anhydrides. Almost all reactions of esters can be recognized as nucleophilic substitutions (in which the carbonyl is retained) or nucleophilic additions (in which the carbonyl is lost)

Answer 32

nucleophiles

Question 33

___, like the other derivatives of carboxylic acids, can be hydrolyzed, yielding carboxylic acids and alcohols. Hydrolysis can take place under either acidic or basic conditions. Under acidic conditions, the first is protonation of the carbonyl oxygen, followed by water attacking the carbonyl carbon

Answer 33

esters

Question 34

Under basic conditions, the nucleophile is OH-, which directly attacks the carbonyl carbon. Triacylglycerols, also called fats or triglycerides, are esters of long-chain carboxylic acids, often called fatty acids, and glycerol (1, 2,3-propanetriol). ___ is the process whereby fats are hydrolyzed under basic conditions to produce soaps

Answer 34

saponification

Question 35

___, such as ammonia, act as a nucleophile and attack the electrophilic carbonyl carbon atom, displacing the ester functional group to yield an amide and an alcohol side-product

Answer 35

nitrogen bases

Question 36

Alcohols can act as ___ and displace the alkoxy groups on esters. This process, which transforms one ester into another, is called transesterification

Answer 36

nucleophiles

Question 37

___ add to the carbonyl groups of esters to form ketones; however, these ketones are more reactive than the initial esters and are readily attacked by more Grignard reagent. Two equivalents of Grignard reagent can thus be used to produce tertiary alcohols with good yield. The intermediate ketone can be isolated only if the alkyl groups are sufficiently bulky to prevent further attack. This reaction proceeds via nucleophilic substitution followed by nucleophilic addition

Answer 37

grignard reagents

Question 38

An important reaction of esters is the Claisen condensation. In the simplest case, two moles of ethyl acetate react under basic conditions to produce a beta-keto ester, ethyl 3 -oxobutanoate, which is also known by its common name, acetoacetic ester. (The Claisen condensation is also called the acetoacetic ester condensation.) The reaction proceeds by addition of an ___ to the carbonyl group of another ester, followed by displacement of ethoxide ion.

Answer 38

enolate anion

Question 39

Esters may be reduced to ___ with LAH, but not with NaBH4. This allows for selective reduction in molecules with multiple functional groups. Note that different alcohols are produced from the ester alkoxy functional group and the carbonyl-containing carbon chain

Answer 39

primary alcohols

Question 40

While phosphoric acid derivatives are not carboxylic acid derivatives, they form esters with many similar properties and reactivities.
Phosphoric acid and the mono- and diesters are acidic (more so than carboxylic acids) and usually exist as anions. Like carboxylic acid esters, under acidic conditions they can be cleaved into the parent acid (here, H3PO4) and alcohols.
Phosphate esters are found in living systems in the form of phospholipids (phosphoglycerides), in which glycerol is attached to two carboxylic acids and one phosphoric acid.
___ are the main component of cell membranes, and phosphate/carbohydrate polymers form the backbone of nucleic acids, the hereditary material of life. the nucleic acid derivative adenosine triphosphate (ATP) can give up and regain one or more phosphate groups. ATP facilitates many biological reactions by releasing phosphate groups to other compounds, thereby increasing their reactivities

Answer 40

phospholipids

Question 41

___ are compounds with the general formula RCONR2, in which the R group can be either a hydrocarbon, a hydrogen, or one of each. Amides are particularly important in biological systems, as the peptide bonds that link amino acids into proteins are actually amide bonds. Amides are named by replacing the -oic acid ending with -amide. Alkyl substituents on the nitrogen atom are listed as prefixes, and their location is specific with the letter N. N-methylpropanamide has a methyl and a hydrogen as the substituents on the nitrogen and a 3-carbon chain, including the carbonyl

Answer 41

amides

Question 42

Although amides do not have an -OH group, those that have hydrogens as ___ on the amide nitrogen have the ability to form hydrogen bonds. In fact, when two hydrogens are present on the amide nitrogen, it has the ability to form twice as many hydrogen bonds as the corresponding carboxylic acid. As a result, amides have very high melting and boiling points, and good water solubility (with the exception of tertiary amides that have two alkyl groups on the amide nitrogen)

Answer 42

substituents

Question 43

___ are generally synthesized by the reaction of acid chlorides with amines or by the reaction of acid anhydrides with ammonia

Answer 43

amides

Question 44

___ can be readily converted into amides by nucleophilic substitution with amines. An amine such as ammonia attack the carbonyl group displacing chloride. The side product is ammonium chloride, formed from excess ammonia and HCl. Primary and secondary amines can also be used as the nucleophile to create substituted amides; tertiary amines are not able to lose a hydrogen and thus cannot participate in this reaction

Answer 44

acyl halides

Question 45

___ are cleaved by ammonia, producing an amide and a carboxylic acid. The carboxylic acid then further reacts with ammonia to form ammonium carboxylate

Answer 45

anhydrides

Question 46

Nitrogen bases such as ___ act as nucleophile and will attack the electrophilic carbonyl carbon atom, displacing the ester functional group to yield an amide and an alcohol side-product

Answer 46

ammonia

Question 47

Amides are the least reactive of the carboxylic acid derivatives but are still susceptible to ___ attack as well as rearrangements and reductions

Answer 47

nucleophilic

Question 48

___ can be hydrolyzed under acidic conditions, via nucleophilic substitution, to produce carboxylic acids. Under basic conditions amides react to form carboxylates

Answer 48

amides

Question 49

The Hofmann ___ converts amides to primary amines with the loss of the carbonyl carbon as a molecule of CO2. The mechanism involves the formation of a nitrene, the nitrogen analog of a carbene. The nitrene is attached to the carbonyl group and rearranges to form an isocyanate, which under aqueous reaction conditions is hydrolyzed to the amine

Answer 49

rearrangement

Question 50

Amides can be reduced with LAH to the corresponding ___. Notice that this differs from the product f the Hofmann rearrangement in that no carbon atom is lost. Note that, unlike with a carboxylic acid reduction with LAH, the oxygen atom is completely removed

Answer 50

amine

Question 51

The most important ___ of carboxylic acids are acyl halides, anhydrides, esters, and amides. These are listed in order from most reactive (least stable) to least reactive (most stable)

Answer 51

derivatives

Question 52

Acyl Halides can be formed by adding RCOOH + SOCL2, PCl3 or PCl5, or PBr3. They can undergo many different nucleophilic substitutions: H2O yields carboxylic acid, while ROH yields an ester and NH3 yields an ___. They can participate in Friedel-Crafts acylation to form an alkyl aryl ketone. They can be reduced to alcohols or, selectively, to aldehydes

Answer 52

amide

Question 53

___ can be formed by RCOO- + RCOCl (substitution) or by RCOOH + RCOOH (condensation). They can undergo many nucleophilic substitution reactions, forming products that include carboxylic acids, amides, and esters. They can participate in Friedel-Crafts acylation

Answer 53

anhydrides

Question 54

___ formed by acid chlorides or anhydrides + ROH or by RCOOH + ROH. They hydrolyze to yield acids + alcohols; adding ammonia yields an amide. Esters undergo transesterification with alcohol to exchange alkoxy functional group. They react with Grignard reagent (2 moles) to produce a tertiary alcohol. Esters can be formed by the Claisen condensation, analogous to the aldol condensation, which combines two molecules of ester acting both as nucleophile and target. They are very important in biological processes, particularly phosphate esters, which can be found in membranes, nucleic acids, and metabolic reactions

Answer 54

esters

Question 55

___ can be formed by acid chlorides + amines, acid anhydrides + ammonia, or ester + ammonia. They can hydrolyze, yielding carboxylic acids or carboxylate anions. Amides can be transformed to primary amines via Hofmann rearrangement or reduction. They are very important in formation of proteins because all amino acids are linked by amide bonds known as peptide bonds

Answer 55

amide