Chem 263 Dec 3, 2013 Hydrolysis of Esters

H3C O

O

NaOH

H2O H3C O

O

ethyl acetate sodium acetate

Na+ CH3CH2OH

Mechanism:

H3C O

O

OH

O

H3COH

OCH2CH3

H3C O

O

OCH2CH3

H

H3C O

O

Na

The hydroxide anion attacks the carbonyl carbon in the first step, and a tetrahedral intermediate is formed. This process is reversible (so if the negative charge on oxygen comes down and kicks out the OH group instead of ethoxide anion in the second step, we get the starting material again). In the second step, The ethoxide anion is ejected and carboxylic acid is formed. However, under the basic conditions, the proton on carbonxylic acid is abstracted by the ethoxide anion to form carboxylate anion and ethanol. The pKa for acetic acid is 4.5, whereas the pKa of ethanol is 17. Ethoxide is a stronger base, therefore it will deprotonate the acetic acid to give acetate. The process of hydrolyzing esters with base is called saponification. Saponification means process of making soap. When you accidentally pour NaOH in your hand, you feel your hand has a soapy feeling. What occurs is that the fat (triglyceride) in your hand is getting hydrolyzed.

O

O

O

O

R

O

R

O

glycerol triester = triglyceride

O

O

O

O

OR

OR

oleic acid

Chemical structure of alpha-linolenic acid (ALA), an essential omega-3 fatty acid, (18:3Δ9c,12c,15c, which means a chain of 18 carbons with 3 double bonds on carbons numbered 9, 12, and 15). Although chemists count from the carbonyl carbon (blue numbering), biologists count from the n (ω) carbon (red numbering). Note that, from the n end (diagram right), the first double bond appears as the third carbon-carbon bond (line segment), hence the name "n-3". This is explained by the fact that the n end is almost never changed during physiological transformations in the human body, as it is more energy-stable, and other compounds can be synthesized from the other carbonyl end, for example in glycerides, or from double bonds in the middle of the chain.

O

O

O

O

O

O

R

R

R

NaOHH2O

OH

OH

OH

glycerol

+ Na O

O

R

soap

Soaps were originally made as follows. Burn wood and dissolve the residue (potassium carbonate (potash) ) in water. Heat calcium carbonate ( limestone or chalk or sea shells) to make quick lime (CaO). Mixing this with the potassium carbonate gives calcium carbonate (insoluble) and potassium hydroxide (caustic potash). When cooked with fat potassium hydroxide will produce soap

wood CO2 H2O

K2CO3CaCO3

CaO KOH FAT Soap Crude soap curds contain glycerol and excess alkali as well, but the soap can be purified by boiling with water and adding NaCl to precipitate the pure sodium carboxylate salts. The salts are collected, perfume is added and the substance is pressed into bars for household use. Soaps act as cleansers because the two ends of the molecule are very different. The sodium carboxylate end of the long chain fatty acid is ionic and therefore hydrophilic (water-loving). As a result, it tries to dissolve in water. The long chain hydrocarbon on the other hand, is non-polar and hydrophobic (water-fearing). It therefore tries to avoid water and dissolve in grease. The net effect is that soaps are attracted to both water and greases are therefore valuable cleansers.

O- K+

O

non-polar polar When soaps are dispensed into water, the long hydrocarbon chain clusters together in a tangled hydrophobic ball, while the ionic heads on the surface of the cluster stick out into the water layer. These spherical clusters are known as micelles and are shown below. The ball depicts the ionic head (polar end) of the fatty acid (carboxylate salt) whereas the chain represents the hydrocarbon chain (non-polar end). Soap works because it has a polar ‘head’ which interacts with water, and an alkyl non-polar ‘tail’ which can interact with compounds that are non-polar such as grease. Many of these molecules come together to form a micelle, where the polar heads face outward to the water, while the tails point inward. This allows the grease to be dispersed and washed away.

Micelle with some greasy material. The circles represent the polar heads (the –COO-), while the lines represent the non-polar tails (the alkyl chain) 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. In water, a carboxylic acid is usually acidic enough to catalyze the reaction though.

H+

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 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 deprotonate an alpha hydrogen a base is needed that will not attack the carbonyl (ie. act like a nucleophile). This may be achieved by using sterically hindered bases:

K+ -O weakN-

Li+

LDA

strong

Electrophiles reacting with enolates:

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

Cl No SN2E2

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 Above reaction would work with:

OCH3

O

R

OOH

would not work

Lecture Outline 5 - 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. 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.

OCH3

O

NHCH3

Methyl 2-(N-methylamino)benzoate

O

OHN

H3C CH3 2-(N,N-dimethylamino)-2Z-butenoic acid Properties of Amines Amines are polar, and therefore have higher boiling point 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. The pKa of protonated methylamine is around 10.5.

H3C N

H

H

H Is this more or less acidic than ammonium ion? It is less acidic. Higher pKa means less acidity (corresponding amine is more basic) Why is protanated methylamine less acidic than ammonium? Because the alkyl group donates electron density to the nitrogen (inductive donation), which stabilizes the positive charge on nitrogen. Ammonium has only hydrogens on it. H is less electron donating than an alkyl group, therefore the positive charge is less stabilized. Example:

NH3 NH2

H+

The pKa of protonated aniline is 4.6. Is this more or less acidic than methylamine? It is more acidic since the pKa is lower. The increased acidity means it is more likely to give away its proton. Why? Because the nitrogen lone pair in aniline is conjugated into the aromatic ring (resonance stabilization). 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 Halogenation NH3 I2 NI3 This kind of reaction was shown in the demo in a previous class. Aminal and Imine Formation from Ketones and Aldehydes (review – see below also) O

NH2R

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

Alkylation Amines are good nucleophiles and can displace leaving groups in SN2 reactions.

H3NI

SN2H3N

I

NH3

H2N

NH4 For the reaction of ammonia with an alkyl halide, 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

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):

NH2HO Cl

O

NH

HO

O

Alternative syntheses of amines: 1) Reductive amination 2) Reduction of nitriles 3) Reduction of nitro groups 4) Gabriel Synthesis 1) 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 N

NH2CH3

HN

N-methylamphetamine

H2 / Pd

aka methedrine

aka speed

O

O

O

O

O

HN1) NH2CH3

2) H2 / Pd

ecstasy

methylene dioxy group 2) Reduction of nitriles (cyanides) Primary amines can also be formed from the reduction of alkyl cyanides with a reducing agent. The reaction occurs by nucleophilic addition of hydride ion to the carbon of the polar nitrile bond, yielding an imine that undergoes further addition of a second equivalent of hydride to yield the primary amine. The nitrile can be formed from SN2 displacement of an alkyl halide (X = Cl, Br, I) with sodium cyanide (NaCN) as shown below.

R XNaCN

R CN

H2 / Pd

or

NaBH4

or

LiAlH4

R NH2

Alkyl halide (X=Cl, Br, I) nitrile primary amine

C N1) LiAlH4

2) H2OC NH2

H

H The hydrogens that are circled come from the hydrides of LiAlH4, whereas the hydrogens that are on the nitrogen come from the water

An example of this process is in the formation of mescaline. Mescaline or 3,4,5-trimethoxyphenethylamine is a psychedelic hallucinogenic drug. It is found from members of the Cactaceae. The effective human dosage is 200–400 milligrams (3.75 mg/kg), with the effects lasting for up to twelve hours. It is not physically addictive. Users typically experience visual hallucinations and altered states of consciousness, in some cases experienced as pleasurable and illuminating, but in others cases accompanied by feelings of intense fear and anxiety. Addition of sodium cyanide to 3,4,5-trimethoxybenzyl chloride yields the nitrile, which is then reduced with hydrogen gas and palladium to yield mescaline. Since mescaline has no stereogenic centers, it is formed as only a single isomer.

H3CO

H3COOCH3

Cl

NaCNH3CO

H3COOCH3

CN

H2 / Pd H3CO

H3COOCH3

NH2

3,4,5-trimethoxybenzyl chloride Mescaline 3) Reduction of NO2 Amines can be prepared by the reduction of a nitro group. The reduction step can be carried out in many different ways, depending on the circumstances. Catalytic hydrogenation over platinum or palladium is clean but incompatible with the presence of other reducible groups such as double bonds. Lithium aluminum hydride followed by acid treatment is a useful method to obtain amines from nitro groups but incompatible with carbonyl groups present. Other methods involve the use of iron, zinc, or tin in acidic aqueous solutions.

R NO2

H2 / Pd

or

Sn / HCl

or

LiAlH4

R NH2

Example:

NO2 Sn

HCl

NH2

An example is the preparation of amphetamine from benzyl bromide and nitroethane. Treatment of nitroethane with base removes the α-hydrogen to the nitro group forming an anion, which then displaces the bromine in an SN2 type mechanism. The α-hydrogens are easily removed because the nitro group is similar in properties to a carbonyl group and is electron withdrawing making these hydrogen’s acidic. Treatment of the resulting nitro compound with hydrogen gas and palladium then yields amphetamine.

Br

N OO

H

:B

N OONO2 NH2

H2 / Pd

nitroethane benzyl bromide Amphetamine Amphetamine, also known as speed, is a synthetic stimulant that has been used to suppress the appetite, control weight, and treat disorders including narcolepsy and attention-deficit hyperactivity disorder. It is also used recreationally and for performance enhancement (these uses are illegal in most countries). Why would amphetamine not be synthesized in the following manner?

Br

NH3

NH2

Polyalkylations would occur, which would make it very difficult to achieve a good yield of the desired product. 4) Gabriel Synthesis The Gabriel amine synthesis uses phthalimide alkylation in preparing a primary amine from an alkyl halide (where X=Cl, Br, I). Imides (-CONHCO-) are similar to ethyl acetoacetate in that the NH hydrogen is flanked by two carbonyl groups. Thus,

imides are deprotonated by such bases as KOH, and the resultant anions are readily alkylated. Reaction with hydrazine (H2NNH2) of the N-alkylated imide then yields a primary amine product along with a byproduct that is similar to luminol (seen in demo).

R X N

O

OK+

N

O

OR

R NH2HNHN

O

O

H2NNH2

potassium phthalimide N-alkylated imide primary amine An example is the preparation of p-chlorophenylalanine from the chirally pure brominated starting material in the (S) configuration. The phthalimide displaces the bromine in an SN2 mechanism, which is then followed by hydrazine treatment, yielding ( R )-p-chlorophenylalanine as shown below. P-chlorophenylalanine is an unnatural amino acid, which was found to be an aphrodisiac (sexual stimulant).

Cl

O

OHBr

N

O

OK+

H2NNH2

Cl

O

OHNH2

p-chlorophenylalanine Alkaloids Alkaloids are nitrogen-containing substances usually from plant sources. The study of alkaloids provided much of the growth in organic chemistry in the nineteenth century and remains today a fascinating area of research. Many alkaloids have pronounced biological properties, and many pharmaceutical agents used today are derived from naturally occurring amines. Morphine (as shown previously) and related alkaloids from the opium poppy, for example, are used from pain relief. In the next section, we will look at some important and well-known alkaloids from various sources of plant material from the Solanaceae plant family (includes peppers, tobacco, potato, and tomato) including nicotine, solanine, and atropine. 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. In lower concentrations, the substance is a stimulant and is one of the main factors leading to the habit-forming qualities of tobacco smoking. Nicotine

seems to provide both a stimulant and a depressant effect, and it is likely that the effect it has at any time is determined by the mood of the user, the environment and the circumstances of use. 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. A few people fall ill or die each year from eating green potatoes, which is attributed to the consumption of solanine. Potatoes naturally produce solanine as a defense mechanism 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

Generally, atropine lowers the "rest and digest" activity of all muscles and glands regulated by the parasympathetic nervous system. This occurs because atropine is a competitive antagonist of the acetylcholine receptors (Acetylcholine is the neurotransmitter used by the parasympathetic nervous system). Therefore, it may cause swallowing difficulties and reduced secretions. Atropine is the name of the racemic mixture, while the enantiomer shown above (refered to as hyoscyamine) is isolated from Hyoscyamus species known as henbane and from Datura species (e.g. D. stramonium), many of which have trumpet shaped flowers. Scopolamine is closely structurally related to atropine. Isolated from Datura stramonium (Jimson weed), it has been used to help fight sea sickness.

N

H

O

O

OHPh H

O

Scopolamine

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