Chapter 23

Question 1

Interesting and Useful Amines

Answer 1

•Many low molecular weight amines have foul odors.
•Trimethylamine [(CH3)3N], formed when enzymes break down certain fish proteins, has the characteristic odor of rotting fish. That is why we add lemon to fish!
•Putrescine (NH2CH2CH2CH2CH2NH2)and cadaverine (NH2CH2CH2CH2CH2CH2NH2)are both poisonous diamineswith putrid odors. They too are present in rotting fish (and other smelly stuff).
•Naturally occurring amines derived from plant sources are called alkaloids.
Three common alkaloids—Atropine, nicotine, and coniine
•Histamine, a rather simple triaminethat is present in many tissues, is responsible for a wide variety of physiological effects.
•Understanding the physiological properties of histamine has helped chemists design drugs tocounteract some of its undesirable effects. Antihistaminesbind to the same active site as histamine in the cell, but they evoke a different response. Examples are brompheniramineand cimetidine.
•A large number of physiologically active compounds are derived from 2-phenethylamine (C6H5CH2CH2NH2). These compounds include adrenaline, noradrenaline, methamphetamine, and mescaline. Each contains a benzene ring bonded to a two-carbon unit with a nitrogen atom (shown in red).
•Cocaine, amphetamines, and several other addicting drugs increase the level of dopamine in the brain, which results in a pleasurable “high.”With time, the brain adapts to increased dopamine levels, so more drug is required to produce the same sensation.
•Understanding the neurochemistry of these compounds has led to the synthesis and availability of several useful drugs. Examples are fentanyl and sumatripan.

Question 2

Structure & Classification

Answer 2

•Amines are classified as:
––1°, 2°, or , 3° amines:1°, 2°, or , 3° amines: Amines in which 1, 2, or 3 hydrogens of NH3 are replaced by alkyl or aryl groups.
•Amines are further divided into aliphatic, aromatic, and heterocyclic amines:
––AliphaticAliphaticamine:amine: An amine in which nitrogen is bonded only to alkyl groups.
––Aromatic amine:Aromatic amine: An amine in which nitrogen is bonded to one or more aryl groups
–Heterocyclic amine:Heterocyclic amine: An amine in which nitrogen is one of the atoms of a ring.

Question 3

Nomenclature

Answer 3

• Aliphatic amines: replace the suffix -ee of the parent alkane by -amineamine. Note the lack of space.
• The IUPAC system retains the name aniline.
• Among the various functional groups discussed so far, the -NH2 group is one of the lowest in order of precedence.
• Common names for most aliphatic amines are derived by listing the alkyl groups bonded to nitrogen in one word ending with the suffix -amineamine. Note the lack of a space (unlike ethers).
• When four groups are bonded to nitrogen, the compound is named as a salt of the corresponding amine.

Question 4

Chirality of Amines

Answer 4

–If we consider the unshared pair of electrons on nitrogen as a fourth group, then the arrangement of groups around N is approximately tetrahedral.
–An amine with three different groups bonded to N is chiral and exists as a pair of enantiomers and, in principle, can be resolved.
–In practice, however, they cannot be resolved because they undergo pyramidal inversion, which converts one enantiomer to the other.
–Pyramidal inversion is not possible with quaternary ammonium ions, and their salts can be resolved.

Question 5

Physical Properties

Answer 5

•Amines are polar compounds, and both 1° and 2° amines form intermolecular hydrogen bonds.
–N-H- - -N hydrogen bonds are weaker than O-H- - -O hydrogen bonds because the difference in electronegativity between N and H (3.0 - 2.1 =0.9) is less than that between O and H (3.5 - 2.1 = 1.4).

Question 6

Basicity

Answer 6

•All amines are weak bases, and aqueous solutions of amines are basic.
–It is common to discuss their basicity by reference to the acid ionization constant of the conjugate acid.
–Using values of pKa, we can compare the acidities of amine conjugate acids with other acids.

Question 7

Basicity-Aliphatic Amines

Answer 7

•Aliphatic Amines

–note that pKa + pKb = 14

Question 8

Basicity-Aromatic Amines

Answer 8

• Aromatic amines are considerably weaker bases than aliphatic amines.
  •Aromatic amines are weaker bases than aliphatic amines because of two factors:
  –Resonance stabilization of the free base, which is lost on protonation.
  –The greater electron-withdrawing inductive effect of the sp2-hybridized carbon of an aromatic amine compared with that of the sp3-hybridized carbon of an aliphatic amine.
  •Electron-releasing groups, such as alkyl groups, increase the basicity of aromatic amines.
  •Electron-withdrawing groups, such as halogens, the nitro group, and a carbonyl group decrease the basicity of aromatic amines by a combination of resonance and inductive effects.
  –4-Nitroaniline is a weaker base than 3-nitroaniline.
  -The neutral form is stabilized, making protonation less facile.
• Heterocyclic aromatic amines are weaker bases than heterocyclic aliphatic amines.
  –In pyridine, the unshared pair of electrons on N is not part of the aromatic sextet.
  –Pyridine is a weaker base than heterocyclic aliphatic amines because the free electron pair on N lies in an sp2 hybrid orbital (33% s character) and is held more tightly to the nucleus than the free electron pair on N in an sp3 hybrid orbital (25% scharacter).
  –Recall that s character allows + charge to get to the nucleus.

Question 9

Basicity-Guanidine

Answer 9

•Guanidine is the strongest base among the common neutral organic nitrogen-containing compounds.
–Its basicity is due to the delocalization of the positive charge over the three nitrogen atoms.

Question 10

Reaction with Acids

Answer 10

• All small amines, whether soluble or insoluble in water, react quantitatively with strong acids to form water-soluble salts.
• Separation and purification of an amine and a neutral compound.

Question 11

Preparation of Amines—Gabriel Synthesis of 1° Amines

Answer 11

• The Gabriel synthesis is comprised of two steps and uses a nucleophile derived from phthalimideto synthesize 1° amines via nucleophilic substitution.
• The N—H bond of a pthalimide is especially acidic because the resulting anion is resonance stabilized by the two flanking carbonyl groups.
• An acid-base reaction forms a nucleophilic anion that can react with an unhindered alkyl halide in an SN2 reaction to form a substituted product.
• The alkylated imide is then hydrolyzed with aqueous base to give a 1° amine and a dicarboxylate.

Question 12

Preparation of Amines—Reduction of N-Containing Functional Groups

Answer 12

• Recall that amines can be prepared by reduction of nitro compounds, nitriles and amides.
• Because the cyano group is readily introduced by SN2 substitution of alkyl halides with ̄CN, this provides a two-step method to convert an alkyl halide to a 1° amine with one more carbon atom.

Question 13

Preparation of Amines—Reductive Amination

Answer 13

•Reductive amination is a two-step method that converts aldehydes and ketones into 1°, 2°, and 3° amines.
•Consider the reductive amination of an aldehyde or ketone using NH3. There are two distinct parts to this reaction.Preparation of Amines—Reductive Amination
[1] Nucleophilic attack of NH3on the carbonyl group forms an imine.[2] Reduction of the imine forms an amine.
•The most effective reducing agent for this reaction is sodium cyanoborohydride (NaBH3CN); it is even weaker than NaBH4.
•With a 1°or 2°amine as starting material, reductive amination is used to prepare 2° and 3° amines respectively

Question 14

prep of amines

Answer 14

•We have already covered these methods
–nucleophilic ring opening of epoxides by ammonia and amines.–addition of nitrogen nucleophiles to aldehydes and ketones to form imines.
–reduction of imines to amines.
–reduction of amides by to amines by LiAlH4.
–reduction of nitriles to a 1° amine.
–nitration of arenes followed by reduction of the NO2 group to a 1° amine

Question 15

Preparation via Azides

Answer 15

•Alkylation of azide ion.

–Alkylation using the azide ion and reduction.

Question 16

Reaction with HNO2

Answer 16

•Nitrous acid, a weak acid, is most commonly prepared by treating NaNO2 with aqueous H2SO4 or HCl.
•In its reactions with amines, nitrous acid:
–participates in proton-transfer reactions.
–is a source of the nitrosyl cation, NO+, a weak electrophile.
•NO+ is formed in the following way.
–Step 1: Proton transfer to HONO.
–Step 2: Loss of H2O.–We will study the reactions of HNO2 with 1°, 2°, and 3° aliphatic and aromatic amines. The latter are the most important from a synthetic perspective.

Question 17

Amines with HNO2

Answer 17

–3° Aliphatic amines, whether water-soluble or water-insoluble, are protonated to form water-soluble salts
.–3° Aromatic amines: NO+ is a weak electrophile and, as such, participates in EAS.
–2° Aliphatic and aromatic amines react with NO+ to give N-nitrosamines.
•Reaction of a 2° amine to give an N-nitrosamine.
–Step 1: Reaction of the 2° amine (a nucleophile) with the nitrosyl cation (an electrophile).
–Step 2: Proton transfer.
•NO+ is formed in the following way.
–Step 1: Proton transfer to HONO.
–Step 2: Loss of H2O.
–We will study the reactions of HNO2 with 1°, 2°, and 3° aliphatic and aromatic amines. The latter are the most important from a synthetic perspective.

Question 18

1° RNH2 with HNO2

Answer 18

•Formation of a diazonium ion.
Step 1: Reaction of a 1° amine with the nitrosyl cation.
Step 2: Protonation followed by loss of water.
•Aliphatic diazonium ions are unstable and lose N2 to give a carbocation which may:
1. Lose a proton to give an alkene.
2. React with a nucleophile to give a substitution product.
3. Rearrange and then react by Steps 1 and/or 2. Note aqueous environment.

Question 19

Diazomethane

Answer 19

Diazomethane, CH2N2
–A potentially explosive, toxic, yellow gas; it is best represented as a hybrid of two contributing structures.
–In 1894 Von Pechmann, a contemporary of Fischer, reported that treating a carboxylic acid with diazomethane gives a methyl ester.
•Esterification occurs in two steps.
Step 1: Proton transfer to diazomethane.
Step 2: Nucleophilic displacement of N2.

Question 20

Diazomethane Preparation

Answer 20

•Diazomethane is prepared by hydrolysis of an ethereal solution of an N-methyl nitrosamide with aqueous base. The traditional precursor is N-nitroso-N-methylurea. However, nowadays such compounds as N-methyl-N’-nitro-N-nitrosoguanidine and N-methyl-N-nitroso-p-toluenesulfonamide are generally used.

Question 21

Substitution Reactions of Aryl Diazonium Salts – Useful!

Answer 21

• Aryl diazonium salts react with a variety of reagents to form products in which Z (an atom or group of atoms) replaces N2, a very good leaving group.
• The mechanism of these reactions varies with the identity of Z.
• This reaction is regiospecific and therefore all the more valuable.

Question 22

Schiemann/Sandmeyer Reactions

Answer 22

•The Schiemann reaction is the most common method used to introduce a flourine onto an aromatic ring.
•The first step involves creation a diazonium salt with BF4-. This salt is heated giving decomposition of the salt to an aryl flouride, nitrogen and boron triflouride.
•An aryl cation is suspected as an intermediate.
•If a primary aromatic amine is reacted with nitrous acid followed by heating with HCl/CuCl, HBr/CuBr or KCN/CuCN the nitrogen group is replaced by -Cl, -Br, or -CN respectively. This is known as the Sandmeyer reaction.
•CuI and CuF do not give desired replacement products in this reaction.
•Treatment of an arenediazonium ion with KI, generally is the best method to introduce iodine onto an aromatic ring (regioselectively).
•Arenediazonium ions are reduced with hydrophosphorous acid, H3PO2, replacing the diazonium salt with a hydrogen.
Finally, reaction with water can be used to make a phenol

Question 23

Substitution Reactions of Aryl Diazonium Salts

Answer 23

• Regarding the reaction of an aryl diazonium salt with hypophosphorus acid to form benzene, consider the synthesis of 1,3,5-tribromobenzene.
• It is not possible to synthesize 1,3,5-tribromobenzene from benzene by direct bromination; Br is an o,p director, bromination with Br2and FeBr3will not add Br substituents meta to each other on the ring.
• It is possible, however, to add three Br atoms meta to each other when aniline is the starting material.
• Because an NH2group is a very powerful o,p director, three Br atoms are introduced in a single step on halogenation. Then, the NH2group can be removed by diazotization and reaction with H3PO2.
• Diazonium salts provide easy access to many different benzene derivatives. Keep in mind the following four-step sequence, because it will be used to synthesize many substituted benzenes.

Question 24

Diazo Coupling: Electrophilic Substitution with Arenediazonium Salts

Answer 24

•Diazo couplings lead to highly colored compounds (azo dyes)

Question 25

Coupling Reactions of Aryl Diazonium Salts

Answer 25

• Because a diazonium salt is only weakly electrophilic, the reaction only occurs when the benzene ring has a strong electron donor group, such as NH2, NHR, NR2, or OH.
• Although these groups activate both the ortho and para positions, substitution occurs para due to steric effects unless the para position already has another substituent.
• To determine what starting materials are needed to synthesize a particular azo compound, always divide the molecule into two components: one has a benzene ring with a diazonium ion, and one has a benzene ring with a very strong electron donor group.

Question 26

Natural and Synthetic Dyes

Answer 26

• Many common synthetic dyes, such as alizarine yellow R, para red, and Congo red, are azo compounds are made via diazonium coupling.
• A Famous / Infamous synthetic dye: Butter Yellow
• Three natural dyes known for centuries are indigo, tyrian purple, and alizarin.
• In 1856 William Henry Perkin synthesized mauveine, a mixture of two compounds that differ only in the presence of one methyl group on one of the aromatic rings.
• To be classified as a dye, a compound must be colored and it must bind fabric.
• Compounds that bind to fabric by some type of attractive force are called direct dyes.
• The attractive forces may be electrostatic interactions, van der Waals forces, hydrogen bonding, and sometimes even covalent bonding—the type of interaction depends on the structure of the dye and the fiber.
• A compound that may be good for dying wool or silk, both polyamides, may be poor for dying cotton, a carbohydrate.
• Wool and silk contain charged functional groups, such as NH3+and COO ̄. Thus, they bind to ionic dyes by electrostatic interactions.
• Positively charged NH3+groups bonded to the protein backbone are electrostatically attracted to anionic groups in a dye like methyl orange.
• Cotton, on the other hand, binds dyes by hydrogen bonding interactions with its many OH groups. Thus, Congo red is bound to the cellulose backbone by hydrogen bonds.

Question 27

Sulfa Drugs

Answer 27

• In 1935, Gerhard Domagk first used a synthetic dye, prontosil, to kill bacteria., including for his 6-year old daughter Hildegarde.
• Prontosil and other sulfur containing antibiotics are collectively known as sulfa drugs.
• Prontosil is not the active ingredient itself—in cells, it is metabolized to sulfanilamide, the active drug.
• To understand how sulfanilamide functions as an antibacterial agent, we must examine folic acid, which microorganisms synthesize from p-aminobenzoic acid.Sulfa Drugs
• Sulfanilamide and p-aminobenzoic acid are similar in size and shape and have related functional groups.
• When sulfanilamide is administered, bacteria attempt to use it in place of p-aminobenzoic acid to synthesize folic acid. Derailing folic acid synthesis means that the bacteria cannot grow and reproduce. Sulfanilamide only affects bacterial cells, because humans do not synthesize folic acid, but rather obtain it from their diets.