NTA Level 5 • Semester 1 • PST05106

Phenols of Pharmaceutical Importance

Pharmaceutical Organic Chemistry • Source Session/Topic 19

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Session 19: Phenols of Pharmaceutical Importance.

Total Session Time: 120 minutes

Prerequisites

• None

Learning Tasks

By the end of this session students are expected to be able to:

• Define phenols

• List phenols and their isomers

• Explain nomenclature of phenols

• Draw chemical structure of phenols

• List chemical properties of phenols

• Explain chemical reactions of phenols

Resources Needed:

• Flip charts, marker pens, and masking tape.

• Black/white board and chalk/whiteboard markers.

SESSION OVERVIEW

SESSION CONTENTS.

STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)

READ or ASK students to read the learning tasks and clarify

ASK students if they have any questions before continuing.

STEP 2: Definition of Phenols (10 minutes).

|Activity: Brainstorming (5 minutes) |

| |

|Ask students to brainstorm on the following question: |

| |

|What are Phenols? |

| |

|ALLOW few students to respond. |

| |

|WRITE their responses on the flip chart/ board. |

| |

|CLARIFY and SUMMARISE by using the content below |

• Phenols are organic compounds which contain a hydroxyl (—OH) group

attached to a carbon atom in a benzene ring.

• Their chemical behaviour is very distinct from that of alcohols, because

they are not capable of undergoing the same oxidation reactions that

alcohols participate it.

• Also, unlike alcohols, phenols are weak acids, since the phenoxide anion

generated by the loss of the hydroxyl proton is resonance-stabilized:

[pic]

• Phenol is the active ingredient in some treatments for sore throats and

is found in several lozenges and throat sprays.

• It is used in the manufacture of many other compounds, such as aspirin,

and Bakelite.

STEP 3: Phenols and their Isomers (10 minutes).

• Cresol is a trivial name for the three isomeric methylphenols.

ortho-Cresol

[pic]

• The structure shown above is ortho-cresol, or 2-methylphenol; the other

isomers are shown below.

2,6 xylenol

[pic]

• The cresols are commonly used as solvents, in disinfectants and

deodorizers, and in the manufacture of other compounds (for example, the

BHA and BHT shown below).

• Xylenol is a trivial name given to the six isomeric dimethylphenols.

• The name is derived from xylene, which is the trivial name for the three

isomeric dimethylbenzenes.

• The structure shown above is 2,6-xylenol, or 2,6-dimethylphenol; the

other isomers are shown below.

[pic]

• The xylenols are found in a number of pesticides and are also used in the

manufacture of many other compounds.

STEP 4: Nomenclature of Phenols (15 minutes).

• Locate the position of hydroxyl group attached to the benzene ring.

• Benzene rings attached to more than one hydroxyl groups are labeled with

the Greek numerical prefixes such as di, tri, tetra to denote the number

of similar hydroxyl groups attached to the benzene ring.

• If two hydroxyl groups are attached to the adjacent carbon atoms of

benzene ring, it is named as benzene1, 2-diol

• In case of substituted phenols, we start locating the positions of the

other function groups with respect to the position where the hydroxyl

group is attached. For example, if a methyl group is attached at fourth

carbon atom with respect to hydroxy group; compound is named as, 4-Methyl

phenol.

[pic]

• Depending on the position of substituted functional group with respect to

the hydroxyl group, words like ortho (when the functional group is

attached to the adjacent carbon atom), para (when the functional group is

attached to the third carbon atom from the hydroxyl group), meta (when

the functional group is attached to the second carbon atom from the

hydroxyl group) are also used for the nomenclature of phenols.

• Compounds with two or more –OH groups have special names:

[pic]

• Certain groups, e.g., -COOH, -CHO, -SO3H, if present in the ring, take

priority; the –OH group is then used as a modifying prefix:

STEP 5: Chemical Structure of Phenols (15 minutes).

• The simplest way to draw the structure of phenol is

[pic]

• There is an interaction between the delocalized electrons in the benzene

ring and one of the lone pairs on the oxygen atom.

• This has an important effect on both the properties of the ring and of

the -OH group.

• One of the lone pairs on the oxygen overlaps with the delocalized ring

electron system

[pic]

Giving a structure rather like this

[pic]

• The donation of the oxygen's lone pair into the ring system increases the

electron density around the ring. That makes the ring much more reactive

than it is in benzene itself. That is explored in another page in this

phenol section.

• It also helps to make the -OH group's hydrogen a lot more acidic than it

is in alcohols. That will also be explored elsewhere in this section.

STEP 6: Chemical Properties of Phenols (15 minutes).

|Activity: Buzzing (5minutes) |

| |

|ASK students to pair up and buzz on the following question for 5 |

|minutes. |

| |

|What are the chemical properties of Phenols? |

| |

|ALLOW pairs to respond on the question. |

| |

|WRITE their response on the flip chart/board. |

| |

|CLARIFY and SUMMARIZE by using the content below |

Acidity:

• Phenols are more acidic (pKa»10) than alcohols (pKa»16 – 20), but less

acidic than carboxylic acids (pKa»5).

• The negative charge of the phenolate ion is stabilised by resonance due

to electron delocalisation onto the ring as shown below:

[pic]

• The acidity difference means that it is possible to separate phenols from

alcohols and/or carboxylic acids.

o Mixing an ether solution, of phenol and alcohol or phenol and

carboxylic acid, with dilute base (sodium hydroxide and sodium

bicarbonate, respectively), results in the stronger acid being

converted to its alkali salt, this is then extracted to the aqueous

phase and can be separated from the organic phase.

• Nucleophilic substitution reactions of phenols are generally carried out

under basic conditions as the phenolate ion is a better nucleophile.

Substituent Effects on Acidity

• Substituents, particularly those located ortho or para to the -OH group,

can dramatically influence the acidity of the phenol due to resonance and

/ or inductive effects.

• Electron withdrawing groups enhance the acidity; electron donating

substituents decrease the acidity. The resonance stabilisation of o-

nitrophenol is shown below:

[pic]

| |pKa | | |pKa |

| |10.0| | | |

| |10.0| | |10.2|

| |10.3| | |10.3|

| |8.6 | | |9.4 |

| |7.2 | | |7.2 |

| |8.4 | | | |

Reactivity

|[pic] |The image to the left shows the |

|[pic] |electrostatic potential for phenol. |

| |The redder an area is, the higher the |

| |electron density and the bluer an area is,|

| |the lower the electron density. |

| |The hydroxyl O atom is a region of high |

| |electron density (red) due to the lone |

| |pairs. |

| |The hydroxyl O atom can function as a |

| |nucleophile or Lewis base. |

| |There is low electron density (blue) on H |

| |atom of the hydroxyl group, i.e. H+ |

| |character, therefore phenols are acidic |

| |(pKa ~ 10) |

| |Due to conjugation with the ring, phenols |

| |are more acidic than alcohols (pKa ~ 16). |

| |Removal of the proton generates a |

| |phenolate ion. |

| |Note the increased electron density on the|

| |oxygen compared to the phenol |

STEP 7: Chemical Reactions involving Phenols (35 minutes).

|Activity: Small Group Discussion (15 minutes) |

| |

|DIVIDE students into small groups |

| |

|ASK students to discuss in groups on the following questions |

|What are the chemical reactions involving Phenols? |

| |

|[pic]REFER Students to Book |

| |

|ALLOW students to discuss for 10 minutes |

| |

|ALLOW each group to present for 5 minutes |

| |

|CLARIFY and SUMMARIZE by using the contents below |

Electrophilic Aromatic Substitution Reactions of Phenols

• Phenols are potentially very reactive towards electrophilic aromatic

substitution.

• This is because the hydroxy group, -OH, is a strongly activating, ortho-

/ para- directing substituent.

• Substitution typically occurs para to the hydroxyl group unless the para

position is blocked, then ortho substitution occurs.

• The strong activation often means that milder reaction conditions than

those used for benzene itself can be used (see table below for a

comparison).

• Phenols are so activated that polysubstitution can be a problem (similar

problems occur with anilines).

[pic]

Summary

|Reaction |Phenol |Benzene |

|Nitration |dil. HNO3 in H2O or |HNO3 / H2SO4 |

| |CH3CO2H | |

|Sulfonation |conc. H2SO4 |H2SO4 or SO3 / H2SO4 |

|Halogenation |X2 |X2 / Fe or FeX3 |

|Alkylation |ROH / H+ or RCl / AlCl3 |RCl / AlCl3 |

|Acylation |RCOCl / AlCl3 |RCOCl / AlCl3 |

|Nitrosation |aq. NaNO2 / H+ | |

• Acylation of Phenols

o Phenols are examples of bidentate nucleophiles, meaning that they can

react at two positions:

▪ on the aromatic ring giving an aryl ketone via C-acylation, a

Friedel-Crafts reaction or,

▪ on the phenolic oxygen giving an ester via O-acylation, an

esterification

o Reagents:

|C-acylation: acylating agent (acyl chloride or anhydride) and |

|AlCl3 |

|O-acylation: acylating agent (acyl chloride or anhydride) |

o The product of C-acylation is more stable and predominates under

conditions of thermodynamic control (i.e. when AlCl3 is present).

o The product of O-acylation forms faster and predominates under

conditions of kinetic control.

o O-acylation can be promoted by either:

▪ acid catalysis via protonation of the acylating agent,

increasing its' electrophilicity or

▪ Base catalysis via deprotonation of the phenol, increasing

its' nucleophilicity.

o It is also known that aryl esters readily rearrange to aryl ketones

in the presence of AlCl3, a reaction known as the Fries

rearrangement:

[pic]

• Carboxylation of Phenols (Kolbe-Schmitt reaction)

o Heating the nucleophilic phenolate salt with carbon dioxide under high

pressure / temperature results in regioselective ortho-substitution.

o This process is also known as the Kolbe-Schmitt synthesis.

o O-hydroxybenzoic acid is more commonly known as salicyclic acid.

[pic]

|MECHANISM FOR CARBOXYLATION OF PHENOLS |

| |[pic] |

|The nucleophilic phenolate (reacting | |

|like an enolate) reacts with the | |

|electrophilic carbon of carbon dioxide | |

|in the ortho position (compare this | |

|with an Aldol reaction) | |

| | |

|The non-aromatic | |

|cyclohexadienonecarboxylate | |

|intermediate tautomerises to the more | |

|stable aromatic enol which is further | |

|stabilised by an intramolecular | |

|hydrogen bond. An acidic work-up will | |

|generate the carboxylic acid. | |

• Oxidation of Phenols

o In general, phenols are more easily oxidized than simple alcohols.

o Oxidation can be achieved by reaction with silver oxide (Ag2O) or

chromic acid (Na2Cr2O7), or other oxidizing agents.

o Particularly important are the oxidation of 1,2- and 1,4-benzenediol

(pyrocatechol and hydroquinone, respectively) and their derivatives

(see examples below):

[pic] [pic]

o These types of systems are important in biological redox-systems such

as coenzyme Q and vitamin K.

o Here's a closer look at the two one electron transfers that are

believed to take place when hydroquinone is oxidized to benzoquinone.

|[pic] |Loss of a proton and|

| |an electron |

| |generates a phenoxy |

| |radical |

|[pic] |Loss of a second |

| |proton and a second |

| |electron completes |

| |the oxidation. |

STEP 8: Key Points (05 minutes)

• Phenol, or hydroxybenzene, is the parent compound of the phenols,

consisting of an OH group directly connected to a benzene ring.

• Phenols are more acidic (pKa»10) than alcohols (pKa»16 – 20), but less

acidic than carboxylic acids (pKa»5).

• Phenols are potentially very reactive towards electrophilic aromatic

substitution.

• Phenols undergoes Carboxylation and acetylation chemical reactions.

STEP 9: Evaluation (05 minutes)

• What are phenols?

• List phenols and their isomers.

• Draw chemical structure of phenols.

• List chemical reactions of phenols.

• What is Kolbe-Schmitt reaction?

References

Ternay, A.L (1976). Contemporary Organic Chemistry. Philadelphia, United

States: W.B. Saunders Co.

Morrison R.T and Boyd R N (1997). Organic Chemistry (6th Ed.). New Delhi,

India: Prentice Hall of India

Graham Solomon et al (2014). Organic Chemistry (11th Ed.). New Jeysey,

United States: John Willey and Sons.

Nadendla R. R. (2005). Principles of Pharmaceutical Organic Chemistry. New

Delhi, India: MacMillan Publishers

Bruice Y (2013). Organic Chemistry (7th ed.). New York, United States:

Prentice Hall Pearson.

Delgado J. N. Et al (1998). Wilson and Gisvold's Textbook of Organic

Medicinal and Pharmaceutical Chemistry (10th Ed.). California, United

States: Lippincott Williams

Bhassin S.K, Gupta R.(2013). Pharmaceutical organic chemistry (E-book

Kindle edition). New Delhi, India: Elsevier Publishing Services

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