Module IV: Chemistry of Functional Groups – I (9 hrs)

Halogen Compounds: Preparation of alkyl halides from alkanes and alkenes - Wurtz reaction and Fittig’s reaction - Mechanism of SN

1 and SN2 reactions of alkyl halides – Effect of substrate and

stereochemistry.

Alcohols: Preparation from Grignard reagent - Preparation of ethanol from molasses - Wash, rectified

spirit, absolute alcohol, denatured spirit, proof spirit and power alcohol (mention only) – Comparison of acidity of ethanol, isopropyl alcohol and tert-butyl alcohol - Haloform reaction and iodoform test -Luca’s test - Chemistry of methanol poisoning – Harmful effects of ethanol in the human body.

Phenols: Preparation from chlorobenzene – Comparison of acidity of phenol, p-nitrophenol and pmethoxyphenol – Preparation and uses of phenolphthalein.

Ethers: Preparation by Williamson’s synthesis – Acidic cleavage - Crown ethers (mention only).

Preparation of alkyl halides from alkanes

Alkanes (the most basic of all organic compounds) undergo very few reactions. One of these reactions

is halogenation, or the substitution of single hydrogen on the alkane for a single halogen to form a

haloalkane. When methane (CH4) and chlorine (Cl2) are mixed together in the presence of ultra violet

irradiation, product is formed, chloromethane (CH3Cl).

The reaction proceeds through the radical chain mechanism. The radical chain mechanism is

characterized by three steps: initiation, propagation and termination. Initiation requires an input of

energy but after that the reaction is self-sustaining. The first propagation step uses up one of the

products from initiation, and the second propagation step makes another one, thus the cycle can

continue until indefinitely.

Step 1: Initiation: Initiation breaks the bond between the chlorine molecule (Cl2). For this step to

occur energy must be put in, this step is not energetically favorable. After this step, the reaction can

occur continuously (as long as reactants provide) without input of more energy.

Step 2: Propagation: The next two steps in the mechanism are called propagation steps. In the first

propagation step, chlorine radical combines with a hydrogen on the methane. This gives hydrochloric

acid (HCl, the inorganic product of this reaction) and the methyl radical. In the second propagation

step more of the chlorine starting material (Cl2) is used, one of the chlorine atoms becomes a radical

and the other combines with the methyl radical.

Step 3: Termination: In the termination steps, all the remaining radicals combine (in all possible

manners) to form more product (CH3Cl), more reactant (Cl2) and even combinations of the two

methyl radicals to form a side product of ethane (CH3CH3).

However, the reaction doesn't stop there, and all the hydrogens in the methane can in turn be replaced

by chlorine atoms. Substitution reactions happen in which hydrogen atoms in the methane are

replaced one at a time by chlorine atoms. You end up with a mixture of chloromethane,

dichloromethane, trichloromethane and tetrachloromethane. Precisely because of this reason large

scale synthesis of alkyl halides never utilises this method from alkanes.

When alkanes larger than ethane are halogenated, isomeric products are formed. Thus chlorination of

propane gives 45% 1-chloropropane and 55% 2-chloropropane. If it is bromination (light-induced at

25 ºC), 2-bromopropane accounts 97% of the mono-bromo product. These results suggest strongly

that 2º-hydrogens are inherently more reactive than 1º hydrogens, the reason being the higher stability

of secondary free radical over the primary.

Preparation of alkyl halides from alkenes

Hydrogen halide addition to an alkene: Halogen halides add across carbon‐carbon double bonds.

These additions follow Markovnikov's rule, which states that the positive part of a reagent (a

hydrogen atom, for example) adds to the carbon of the double bond that already has more hydrogen

atoms attached to it. The negative part adds to the other carbon of the double bond. Such an

arrangement leads to the formation of the more stable carbocation over other less‐stable intermediates.

Benzylic and allylic sites (which are resonance stabilised) are exceptionally reactive in free radical

halogenation reactions.

The brominating reagent, N-bromosuccinimide (NBS), has proven useful for achieving allylic or

benzylic substitution.

Wurtz reaction is an organic reaction used to couple two alkyl halides to form an alkane using

sodium metal.

The mechanism begins with a single electron transfer (SET) from sodium metal to the alkyl halide,

which dissociates to form an alkyl radical and sodium halide salt. Another molecule of sodium

performs another SET to the alkyl radical to form a nucleophilic carbanion. The carbanion then

attacks another molecule of alkyl halide in a nucleophilic substitution reaction (SN2) to form the final

coupled product and another molecule of sodium halide salt.

Limitations:

One can prepare higher alkanes with even number of carbon atoms only, by this method

If two different alkyl halides are treated with sodium metal in presence of dry ether then mixture

of three different products is obtained.

Fittig reaction is an extension to the Wurtz reaction wherein two aryl halides couple using sodium

metal.

If a mixture of aryl halide and alkyl halide is coupled together in presence of sodium metal, its called

Wurtz–Fittig reaction.

SN1 mechanism or dissociative mechanism

SN1 indicates a substitution, nucleophilic, unimolecular reaction. In an SN

1 there is loss of the leaving

group generates an intermediate carbocation which is then undergoes a rapid reaction with the

nucleophile. In an SN1 reaction, the rate determining step is the loss of the leaving group to form the

intermediate carbocation. The more stable the carbocation is, the easier it is to form, and the faster

the SN1 reaction will be.

The C-X bond breaks first, before the nucleophile approaches. This results in the formation of a

carbocation. because the central carbon has only three bonds, it bears a formal charge of +1. Recall

that a carbocation should be pictured as sp2 hybridized, with trigonal planar geometry. Perpendicular

to the plane formed by the three sp2 hybrid orbitals is an empty, unhybridized p orbital.

In the second step of this two-step reaction, the nucleophile attacks the empty, 'electron hungry' p

orbital of the carbocation to form a new bond and return the carbon to tetrahedral geometry.

In the model SN1 reaction shown above, the leaving group dissociates completely from the vicinity of

the reaction before the nucleophile begins its attack. Because the leaving group is no longer in the

picture, the nucleophile is free to attack from either side of the planar, sp2-hybridized carbocation

electrophile. This means that about half the time the product has the same stereochemical

configuration as the starting material (retention of configuration), and about half the time the

stereochemistry has been inverted. In other words, racemization has occurred at the carbon center.

Influence of the solvent in an SN1 reaction: A polar protic solvent is highly positively charged, it can

speed up the rate of the unimolecular substitution reaction because the large dipole moment of the

solvent helps to stabilize the inermediate. Since the carbocation is unstable, anything that can stabilize

this even a little will speed up the reaction. And also the highly positive and highly negative parts

interact with the substrate to lower the energy of the transition state.

Influence of the substrate in an SN1 reaction: In the SN

1 reaction, the big barrier is carbocation stability.

Since the first step of the SN1 reaction is loss of a leaving group to give a carbocation, the rate of the

reaction will be proportional to the stability of the carbocation. Carbocation stability increases with

increasing substitution of the carbon (tertiary > secondary >> primary) as well as with resonance.

SN2 mechanism

The reaction takes place in a single step, and bond-forming and bond-breaking occur simultaneously.

This is called an 'SN2' mechanism. In the term SN

2, S stands for 'substitution', the subscript N stands

for 'nucleophilic', and the number 2 refers to the fact that this is a bimolecular reaction: the overall

rate depends on a step in which two separate molecules (the nucleophile and the electrophile) collide.

The nucleophile, being an electron-rich species, must attack the electrophilic carbon from the back

side relative to the location of the leaving group. Approach from the front side simply doesn't work:

the leaving group - which is also an electron-rich group - blocks the way. The result of this backside

attack is that the stereochemical configuration at the central carbon inverts as the reaction

proceeds. In a sense, the molecule is turned inside out. At the transition state, the electrophilic carbon

and the three 'R' substituents all lie on the same plane.

Influence of the solvent in an SN2 reaction: The rate of an SN

2 reaction is significantly influenced by

the solvent in which the reaction takes place. The use of protic solvents (those, such as water or

alcohols, with hydrogen-bond donating capability) decreases the strength of the nucleophile, because

of strong hydrogen-bond interactions between solvent protons and the reactive lone pairs on the

nucleophile. A less powerful nucleophile in turn means a slower SN2 reaction. SN

2 reactions are faster

in polar aprotic solvents: those that lack hydrogen-bond donating capability.

Influence of the substrate in an SN2 reaction: In the SN

2 reaction, the big barrier is steric hindrance.

Since the SN2 proceeds through a backside attack, the reaction will only proceed if the empty orbital is

accessible. The more groups that are present around the vicinity of the leaving group, the slower the

reaction will be. That’s why the rate of reaction proceeds from primary (fastest) > secondary >>

tertiary (slowest)

Preparation of Alcohols from Grignard reagent

Alkyl Magnesium halides are called Grignard reagents (RMgX). Grignard reagents on reaction with

Carbonyl compounds form alcohols.

Grignard reagent on reaction with formaldehyde forms primary alcohol.

Grignard reagent on reaction with aldehydes forms secondary alcohols.

Grignard reagent on reaction with ketones forms tertiary alcohols.

Preparation of ethanol from molasses

Ethanol is a volatile, flammable, clear, colourless liquid. It is used as a germicide, beverage,

antifreeze, fuel, solvent, depressant and chemical intermediate. It can be made by the fermentation

process of material that contains sugar or from the compound which can be converted to sugar. Yeast

enzyme readily ferment sucrose to ethanol.

Molasses is the mother liquor left after the crystallization of sugarcane juice. It is a dark coloured

viscous liquid. Molasses contains about 60% fermentable sugar. It is first diluted with water in 1:5

(molasses: water) ratio by volume. If nitrogen content of molasses is small, it is now fortified with

ammonium sulphate to provide adequate supply of nitrogen to yeast. Fortified solution of molasses is

then acidifies with small quantity of sulphuric acid. Addition of acid favours the growth of yeast but

unfavours the growth of useless bacteria. Yeast is added to it at 30O C and kept for 2 to 3 days.

During this period, enzymes invertase and zymase which are present in yeast, convert sugar into ethyl

alcohol. Alcohol obtained by the fermentation is called WASH, which is about 15% to 18% pure.

Rectified spirit, also known as neutral spirits or rectified alcohol, is highly concentrated ethanol

which has been purified by means of repeated distillation of wash, a process that is called

rectification. The purity of rectified spirit has a practical limit of 97.2% ABV (95.6% by mass) when

produced using conventional distillation processes, because a mixture of ethanol and water becomes a

minimum-boiling azeotrope at this concentration. (ABV = alcohol by volume)

Absolute or anhydrous alcohol refers to ethanol with low water content of maximum water contents

ranging from 1% to a few parts per million (ppm) levels. Its prepared through azeotropic distillation

of rectified spirit. Absolute alcohol is not intended for human consumption. Absolute ethanol is used

as a solvent for laboratory and industrial applications, where water will react with other chemicals,

and as fuel alcohol.

Ethyl alcohol (ethanol) made undrinkable by the addition of very bad-tasting chemicals (denaturants)

which usually also have offensive odor, such as butyl alcohol, gasoline, kerosene, methanol, or

pyridine is called denatured spirit. The objective of denaturing is to escape the excise duty levied on

drinkable ethanol. It is also called methylated spirit.

Why take a pure product and make it toxic? Basically, it's because alcohol is regulated and taxed by

many governments. Pure alcohol, if it was used in household products, would offer a much less

expensive and readily available source of ethanol for drinking. If alcohol wasn't denatured, people

would drink it.

Proof spirit an alcoholic liquor containing one half of its volume of alcohol of a specific gravity

of.7939 at 60° F.

Power alcohol is mixture liquid. The major use of power alcohol is found in the automobiles as they

generate energy from it for their operation. It act as a good fuel for the automobiles and is formed by

mixing the petrol and ethyl alcohol in the fixed ratio. The ratio to make power alcohol is 75% petrol

and 25% ethyl alcohol.

Comparison of acidity of ethanol, isopropyl alcohol and tert-butyl alcohol

There are two factors deciding the acidity of alcohols; Inductive effect Solvation

Positive inductive effect of the alkyl groups in alcohols decreases the stability of conjugate base

(alkoxide ion) and in tert-butanol three methyl group increases electron density and hence decreases

stability most. In case of ethanol there is only one methyl group while in isopropyl alcohol its two.

Hence the alkoxide ion of tert-butanol will be least stable followed by isopropyl alcohol and ethanol.

Another reason is solvation .With an unhindered alcohol,water molecules can easily surround ,solvate

and hence stabilize the alkoxide anion that would form by the loss of the alcohol proton to a base .But

if the alkyl group is bulky ,salvation of the alkoxide anion is hindered as in ter-butoxide anion . Hence

the alkoxide ion of tert-butanol will be least stable followed by isopropyl alcohol and ethanol.

Acidity will be in the order;

Ethanol >isopropyl alcohol > tert-butyl alcohol

Haloform reaction and iodoform test

The haloform reaction is the reaction of a methyl ketone with chlorine, bromine, or iodine in the

presence of hydroxide ions to give a carboxylate ion and a haloform. There is one aldehyde that

undergoes the haloform reaction, which is acetaldehyde.

When the halogen used is iodine, the haloform reaction (Nucleophilic substitution) can be used to

identify methyl ketones because iodoform is a yellow solid with a characteristic odor. The test is

known as the iodoform test. The reaction proceeds via successively faster halogenations at the α-

position until the 3 H have been replaced. The halogenations get faster since the halogen stablises the

enolate negative charge and makes it easier to form.

Alcohols that have the general structural formula 1 also give a positive iodoform test because, under

the reaction conditions, they are oxidized (see oxidation) to the corresponding methyl ketone, or, in

the case of ethanol to acetaldehyde, which is the only aldehyde that undergoes haloform reaction.

Any compounds containing the CH3C=O group or the CH3CH(OH) group give a positive result with

the iodoform test. When I2 and NaOH is added to a compound containing one of these groups, a pale

yellow precipitate of iodoform (triiodomethane) is formed. The iodoform test can therefore be used

to identify aldehydes and ketones; is the compound is an aldehyde then it must be ethanal (this is

the only aldehyde with the CH3C=O group). This occurs as three I atoms replace the H atoms of

CH3C=OR, and the C-C bond breaks due to the electron withdrawing effect of the three I atoms (as I

is more electronegative than C) forming CHI3 and the salt anion of a carboxylic acid.

This test can also be used to identify alcohols; if the alcohol is a tertiary alcohol then it gives no

result as it cannot be be oxidised. If the alcohol is a primary alcohol then it must be ethanol (as this is

oxidised to ethanal, which is the only aldehyde that gives a positive result with the iodoform test). All

secondary alcohols give a positive result, as they are oxidised to ketones.

Luca’s test

HCl + Anhydrous ZnCl2 is known as Lucas Reagent. It is used to determine the DEGREE of an

alcohol.

The alcohol is reacted with Lucas reagent, and gives alkyl halide along with water. The reaction

follows SN1 mechanism, and a carbocation intermediate is formed, the stability of which determines

the rate of the reaction. The alkyl halide formed is insoluble, and its formation causes the solution to

become turbid, ie. cloudy.

Now, Tertiary alcohols (which give 3 degree carbocations) and alcohols which give very stable

carbocations on losing water after protonation (eg. resonance stabilised carbocations) react fastest and

give immediate turbidity. Eg: t-butyl alcohol

Secondary alcohols react a bit slower as their carbocations (2 degree) are not as stable as above

mentioned ones. They give turbidity after about 5-10 minutes. Eg.: isopropyl alcohol

Primary alcohols react very slowly (1 degree carbocations are very unstable), and their turbidity

comes after more than 45 minutes, and this is why they are said to produce no turbidity in the reaction

mixture. Eg: Ethanol

This way, degree of an alcohol can be found.

Those alcohols which form very unstable carbocations do not give positive lucas test. Eg: phenol,

cyclopropanol, etc.

Chemistry of methanol poisoning

Methanol is not toxic itself, but it is metabolized to become highly toxic formic acid and its anion

formate. Formic acid can create a metabolic acidosis, and both formic acid and formate inhibit the

respiration chain in the mitochondria of the cells in the human body.

This results in a more severe acidosis and multiple organ failure, usually affecting the brain and the

vision first. Treatment is focused on blocking the enzyme alcohol dehydrogenase (ADH) with either

ethanol or fomepizole, buffering the metabolic acidosis with bicarbonate, and using dialysis to remove

methanol and formate, as well as to correct the metabolic acidosis. Folinic (or folic) acid may also be

given to enhance the endogenous metabolism of formate.

A buffer (usually bicarbonate) is used to treat the acidic blood and other body tissues. This reduces

the acid levels in the body and also reduces toxicity of formic acid/formate (the product of

metabolised methanol), thus hopefully temporarily reversing the symptoms. However, this will

usually only postpone symptoms and the problem will most often not be solved until the metabolism

of methanol is blocked. Ethanol (regular alcohol) is the most commonly used antidote to block the

metabolising of methanol.

Harmful effects of ethanol in the human body

Digestive and endocrine glands: Drinking too much alcohol can cause abnormal activation of digestive enzymes produced by the pancreas. Buildup of these enzymes can lead to inflammation

known as pancreatitis. Pancreatitis can become a long-term condition and cause serious complications.

Inflammatory damage: The liver is an organ which helps break down and remove harmful substances from your body, including alcohol. Long-term alcohol use interferes with this process. It also increases your risk for chronic liver inflammation and liver disease. The scarring caused by this inflammation is known as cirrhosis. The formation of scar tissue destroys the liver. As the liver becomes increasingly damaged, it has a harder time removing toxic substances from your body.

Sugar levels: The pancreas helps regulate your body’s insulin use and response to glucose. When your pancreas and liver aren’t functioning properly, you run the risk of experiencing low blood sugar,

or hypoglycemia. A damaged pancreas may also prevent the body from producing enough insulin to utilize sugar. This can lead to hyperglycemia, or too much sugar in the blood.

Central nervous system: One of the easiest ways to understand alcohol’s impact on your body is by understanding how it affects your central nervous system. Slurred speech is one of the first signs you’ve had too much to drink. Alcohol can reduce communication between your brain and your body. This makes coordination more difficult. You may have a hard time balancing. You should never drive after drinking. Drinking also makes it difficult for your brain to create long-term memories. It also reduces your ability to think clearly and make rational choices. Over time, frontal lobe damage can occur. This area of the brain is responsible for emotional control, short-term memory, and judgement,

in addition to other vital roles. Chronic and severe alcohol abuse can also cause permanent brain damage. This can lead to Wernicke-Korsakoff syndrome, a brain disorder that affects memory.

Dependency: Some people who drink heavily may develop a physical and emotional dependency on alcohol. Alcohol withdrawal can be difficult and life-threatening. You often need professional help to break an alcohol addiction. As a result, many people seek medical detoxification to get sober. It’s the safest way to ensure you break the physical addiction. Depending on the risk for withdrawal

symptoms, detoxification can be managed on either an outpatient or inpatient basis.

Symptoms of alcohol withdrawal include:

anxiety nervousness nausea tremors high blood pressure irregular heartbeat heavy sweating

Seizures, hallucinations, and delirium may occur in severe cases of withdrawal.

Digestive system: The connection between alcohol consumption and your digestive system might not

seem immediately clear. The side effects often only appear after there has been damage. And the more you drink, the greater the damage will become. Drinking can damage the tissues in your digestive tract and prevent your intestines from digesting food and absorbing nutrients and vitamins. As a result, malnutrition may occur.

Heavy drinking can also lead to:

gassiness bloating a feeling of fullness in your abdomen diarrhea or painful stools

For people who drink heavily, ulcers or hemorrhoids (due to dehydrationand constipation) aren’t

uncommon. And they may cause dangerous internal bleeding. Ulcers can be fatal if not diagnosed and treated early. People who consume too much alcohol may also be at risk for cancer. People who drink frequently are more likely to develop cancer in the mouth, throat, esophagus, colon, or liver. People who regularly drink and use tobacco together have an even greater cancer risk.

Circulatory system: Alcohol can affect your heart and lungs. People who are chronic drinkers of alcohol have a higher risk of heart-related issues than people who do not drink. Women who drink are more likely to develop heart disease than men who drink.

Circulatory system complications include:

high blood pressure

irregular heartbeat difficulty pumping blood through the body stroke heart attack heart disease heart failure

Difficulty absorbing vitamins and minerals from food can cause anemia. This is a condition where you have a low red blood cell count. One of the biggest symptoms of anemia is fatigue.

Skeletal and muscle systems: Long-term alcohol use may prevent your body from keeping your bones strong. This habit may cause thinner bones and increase your risk for fractures if you fall. And factures may heal more slowly. Drinking alcohol may also lead to muscle weakness, cramping, and eventually atrophy.

Immune system: Drinking heavily reduces your body’s natural immune system. This makes it more

difficult for your body to fight off invading germs and viruses. People who drink heavily over a long period of time are also more likely to develop pneumonia or tuberculosis than the general population. About 10 percent of all tuberculosis cases worldwide can be tied to alcohol consumption. Drinking alcohol also increases your risk for several types of cancer, including mouth, breast, and colon. Click here to learn the basics of alcoholism. You can also read about the stages of alcoholism and recognizing an addiction.

Phenols: Preparation from chlorobenzene

When chlorobenzene is heated with caustic soda at 3000C and 200 atm pressure, sodium phenoxide is formed which on acidification produces phenol. Its called Dows process.

The reaction passes through a benzyne intermediate which was obtained on proton abstraction followed by leaving of the chloride ion from chorobenzene. The benzyne intermediate on nucleophilic attack of a hydroxyl group followed by a ring protonation furnishes phenol.

Benzyne is a highly reactive intermediate which differs from benzene in having two less hydrogen and

an extra bond between two ortho carbons. Benzyne reacts rapidly with any available nucleophile.

Comparison of acidity of phenol, p-nitrophenol and p-methoxyphenol

Phenol is a very weak acid and the position of equilibrium lies well to the left. Phenol can lose a

hydrogen ion because the phenoxide ion formed is stabilised by resonance since one of the lone pairs

on the oxygen atom overlaps with the delocalised electrons on the benzene ring. The more stable the

ion is, the more likely it is to form.

p-nitrophenol is more acidic than phenol because the nitro- group is a strongly electron

withdrawing group. This causes the negative charge on the p-nitrophenoxide ion to be in better

delocalisation than that of phenol.

p-methoxyphenol is less acidic than phenol because the methoxy- group is strongly electron

donating. This causes the negative charge on the p-methoxyphenoxide to be in a poor delocalisation

than in phenol.

Order of acidity: p-nitrophenol > phenol > p-methoxyphenol

Preparation and uses of phenolphthalein

Phenolphthalein is synthesized by electrophilic aromatic substitution of phthalic anhydride and 2

equivalents of phenol in the presence of concentrated sulfuric acid at 90°C to yield the product,

phenolphthalein.

Mechanism

Phenophthalein is an acid-base indicator. It is often used for titration. It is pink in basic solution and

colourless in neutral and acidic solution.

Preparation of Ether by Williamson’s synthesis

The Williamson ether synthesis is an organic reaction used to convert an alcohol and an alkyl halide

to ether using a base such as NaOH. The mechanism begins with the base abstracting the proton from

the alcohol to form an alkoxide intermediate. The alkoxide then attacks the alkyl halide in a

nucleophilic substitution reaction (SN2), which results in the formation of the final ether product.

Mechanism

Reactions of Ethers: Acidic Cleavage