Chem 263 Dec 6, 2016 Conversion of Acids to Esters The following reaction occurs in bad wine (wine containing acetic acid).

H3C OH

O

OH+

H3C O

O

HO

H+

Acetic acid Ethanol Ethyl Acetate Mechanism:

H3C OH

O

OH

H+

C

O

O

OHH3C

HOH2

H+H3C O

O

HO

H

O+

H

H H

Would an ester be formed under basic conditions?

H3C OH

O

OH+

H3C O-

O+

Acetic acid Ethanol Sodium AcetateUnreactive

Na+ -OH

H2O Na+ OH

There is no ester formation from a carboxylic acid with a base. A salt is obtained instead. In water, a carboxylic acid is usually acidic enough to catalyze the reaction though. Reactions at the α Carbon Compare the pKa’s of the alpha hydrogens of an ester and a ketone:

OR'

O

R

H H

pKa ~ 25

R'

O

R

H H

pKa ~ 20

H+

The ketone is more acidic. This can be explained by the resonance structures of the enolate (2 major forms and one minor form):

OR'

O

R

H H

Base

OR'

O

R

H

OR'

O

R

H

OR'

O

R

H(minor)

important resonance form To abstract an alpha hydrogen a base is needed that will not act like a nucleophile and attack the carbonyl. This may be achieved by using sterically hindered bases:

K+ -O weakN-

Li+

LDA

strong

Electrophiles reacting with enolates (exactly analogous to ketone and aldehydes):

OR'

O

R

H H

LDA

OR'

O

R

H

E+

OR'

O

R

H E

Reaction Electrophile Acts as 'E+'

Halogenation X2 X = Cl, Br, I X+

Alkylation R-CH2-X RCH2+

Aldol C CHR

O

R H

OH

Acylation C CYR

O

R

O

Examples: Halogenation

CH2

O

O

H LDA

H2C O

O Cl2

CH2

O

O

Cl

LiCl

HN

Alkylation

H3C OH2C CH3

OLDA

H2C OH2C CH3

O

ClOO

Benzyl chloride

CH2

O

O

H 1. LDACH2

O

O

H3C2. ICH3

SN2 substitution What else could be used (instead of ICH3)?

INo, SN2 reactions won't go with this reagent

IYes, in the above reaction the product would be

Benzyl iodide

CH2

O

OH2C

Aldol

CH2

O

OH 1. LDA

CH2

O

OCH

2. O H

H+

HO H

OH

3.

overall addn of

Mechanism

H3C OH2C CH3

OLDA

H2C OH2C CH3

O

H

O

HO

OO

O

OH O

H H!"

H2OHCl

Acylation

CH2

O

O

H 1. LDACH2

O

O

C

2. O Cl

O

Mechanism

H3C OH2C CH3

OLDA

H2C OH2C CH3

O

O

Cl

O ClO

O

OO

O!

"

Acylating Agents:

R

O

Cl R

O

O

O

R R

O

O R

Amines Nomenclature:

N

H

H H

Ammonia (simplest amine)

N

H

H R

Primary amine

N

H

R R

Secondary amine

N

R

R R

Tertiary amine

N

R

R RR

Quaternary ammonium salt

For simple amines, name the alkyl group (R), and add amine at the end of the nomenclature. Secondary and tertiary amines in which R groups are all the same are simpled named as di- or trialkylamines. Amines bearing different R groups are named by ordering the groups alphabetically. Examples: H3C NH2 Methylamine

N

HN

Triethylamine Allylbenzylamine

You should know the three structures below:

NH2

N N

HN

Aniline Pyridine Imidazole

OCH3

NH2

O

Methyl 2-aminobenzoate. It has the flavour of grapes, and also repels geese. Benzoic acid numbering used on aromatic ring Note that the ester group takes priority as parent structure, rather than the amine. Then you count around the ring to give the lowest substitution number. In this case, C2 is where the amine is substituted.

NH3C CH3

CH3 Trimethylamine

O

OH

NH2H

The structure shown above is an α-amino acid, named L-alanine. It is a major constituent of spider silk. The systematic name for alanine is (S)-2-aminopropanoic acid.

Properties of Amines Amines are polar, and therefore have higher boiling points than hydrocarbons of similar molecular weight. Small amines tend to be water soluble, while larger amines containing more carbons are usually soluble in acid. Amines have a lone pair and are both nucleophiles and bases, so they will react with acids such as a hydrogen halide to form salts.

H+ X XNR3 NHR3 The pKa for ammonia is about 36.

HNH3 NH2 +amideanion

Ka = [NH2][H+]/[NH3] = 10-36 The pKa for an ammonium ion is about 9.4.

HNH4 NH3 + Ka = [NH3][H+]/[NH4] = 10-9.4 In biology, the acidity of pKa of an amine may be mentioned, but usually they are referring to the ammonium ion and not the amine itself. Example:

H2N NH

NH2

spermidine Spermidine is a polyamine isolated from seminal fluid in males, but occurs in all cells. It reacts with acetic acid that is present in females. Which amine is protonated first? The secondary amine in the middle, since it is the most basic nitrogen (2 alkyl groups donate negative charge through the inductive effect to nitrogen).

Example of diamines:

H2N NH21,3-diaminopropane

H2NNH2

1,4-diaminobutane(putrescine)

H2N NH21,5-diaminopentane

(cadaverine) Some of these diamines occur in rotting meat, warning you not to eat it. Reactions of amines Alkylation Amines are good nucleophiles and can displace leaving groups in SN2 reactions.

H3NI

SN2H3N

I

NH3

H2N

NH4I

Excess

For the reaction of ammonia with an alkyl halide, at least two equivalents of ammonia are needed. One to do the alkylation, and the other one to react with the acidic proton that is produced from the first SN2 reaction (here it is shown as an ammonium salt, it could also occur as an HX acid) For reactions of primary alkyl halides with substituted amines, the alkylation is difficult to stop after the first alkylation because the product amine is also nucleophilic, and usually more so than the starting material. The result is generally a mixture of alkylated products. Depending on how many hydrogens the starting amine has, the alkylation will continue until all protons are removed, or even further to make an ammonium salts. This is usually undesirable as mixtures are often formed.

H3C NH2 H3C NH

CH3

H3C N

CH3

CH3 H3C N

CH3

CH3

CH3

tetraammonium iodide

ICH3I CH3ICH3I

Example:

2-aminoethanol

NH2HO

CH3I(excess)

NH

HO CH3

HI

CH3I NHO CH3

HI

CH3

CH3I

NHO CH3

CH3

CH3

Choline

H3C

O

ClNO CH3

CH3

CH3

O

H3C

Acetylcholineacetylcholinesterase

I

In this example, the nitrogen of amine has alkylated 3 times, whereas the oxygen is not alkylated at all. Alcohols are much less reactive than amines. Oxygen is more electronegative than nitrogen and is less nucleophilic. The oxygen can be alkylated by making an alkoxide anion and then adding yet more methyl iodide. Choline can react with acetyl chloride to form acetylcholine, a neurotransmitter. An enzyme called acetylcholinesterase removes the acetyl group in vivo. Parathion and sarin are inhibitors of this enzyme. Parathion is used as an insecticide (which is also toxic to humans), while sarin has been used as a chemical weapon.

OP

O

S

O

NO2

O

PO

CH3F

parathion sarin Amides are more stable than esters, and an amine is more reactive than an alcohol (oxygen is more electronegative than nitrogen): Halogenation NH3 I2 NI3 This kind of reaction was shown in the demo in a previous class. (Explosive product)

Acylation Amines can be acylated by the following:

R Y

O Acid chlorides (Y = Cl)AnhydridesEsters

Cl

O

NCH3H

HN

O

CH3

H

HCl

H2NCH3

NCH3H

H

H

Cl

Note that 2 equivalents of the amine are needed, 1 for the acylation and the second forms a salt with the acid byproduct

Aminal and Imine Formation from Ketones and Aldehydes (review – see below also) O

NH2R

Reductive Amination (via imine formation with ketone or aldehyde) When the carbon-nitrogen double bond (an imine) is reduced to give primary or secondary amine, this process is called reductive amination.

O

R NH2

N

R

+ H2O

1) NaBH4 or LiAlH42) HClorH2 / Pd

HN

R

imine

Examples:

O

O

O

O

O

HN1) NH2CH3

2) H2 / Pd

ecstasy

methylene dioxy group Alkaloids Nicotine is found naturally in tobacco and is shown below. It constitutes 0.3 to 5% of the tobacco plant by dry weight. It is a potent nerve poison and is included in many insecticides. The body converts nicotine into nicotinic acid or better known as niacin. Niacin, also known as vitamin B3, is a water-soluble vitamin whose derivatives such as NADH, NAD, NAD+, and NADP play essential roles in energy metabolism in the living cell and DNA repair. Severe lack of niacin causes the deficiency disease pellagra, whereas a mild deficiency slows down the metabolism, which in turn decreases cold tolerance and is a potential contributing factor towards obesity.

N

NH

body

N

CO2H

Nicotine Nicotinic acid

Solanine is a glycoalkaloid (contains a steroidal alkaloid linked to a sugar) poison found primarily in the green parts of potato (stems, leaves) and greening potatoes. It is very toxic even in small quantities. Studies suggest that 2-5 mg/kg body weight can cause toxic symptoms and a dosage of 3-6 mg/kg body weight can be fatal. Solanine has both fungicidal and pesticide properties, and it is one of the plant's natural defenses against insects, disease, and predators.

N

H

HH

H

OO

OH

OO

HO

O

OOH

OHOH

OH

OHHOHO

Solanine

Atropine is a tropane alkaloid extracted from the deadly nightshade (Atropa belladonna) and other plants of the family Solanaceae. It is a secondary metabolite of these plants and serves as a drug with a wide variety of effects. Being potentially deadly, it derives its name from Atropos, one of the three Fates who, according to Greek mythology, cut the thread of life. In the Renaissance times, women used the juice of the berries of Atropa belladonna to enlarge the pupils of their eyes, for cosmetic reasons; "belladonna" is Italian for "beautiful lady".

N

H

O

O

OHPh H

Atropine

Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant (Erythroxylum coca). This is not in the Solanaceae family, but rather is in family Erythroxylaceae. It is a stimulant of the central nervous system and an appetite suppressant, creating what has been described as a euphoric sense of happiness and increased energy. Though most often used recreationally for this effect, cocaine is also a topical anesthetic that was used in eye and throat surgery in the 19th and early 20th centuries. Cocaine is addictive, especially in free base form (e.g. Crack). Shown below are two representations of cocaine:

N CO2CH3H

H

O

O NH3C OOCPh

OOCH3

Cocaine The addictive properties of cocaine hindered its use as an anesthetic. Derivatives were synthesized to isolate the anesthetic properties from the addictive properties. Novocain and Benzocaine are non-addictive, local anesthetics commonly used in dentistry and as a topical pain reliever respectively.

NH2

O

O

NH2

O

ON

Novocaine Benzocaine