Upload
others
View
11
Download
0
Embed Size (px)
Citation preview
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Soaps were originally made as follows.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