NTA Level 5 • Semester 1 • PST05106

Aryl Halides of Pharmaceutical Importance

Pharmaceutical Organic Chemistry • Source Session/Topic 20

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Session 20: Aryl Halides 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 aryl halides

• Explain nomenclature of aryl halides

• Draw chemical structure of aryl halides

• List chemical properties of aryl halides

• Explain chemical reactions of aryl halides

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 Aryl Halides (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 |

Aryl halides are the compounds that contain halogen atom directly attached

to the benzene ring. They have general formula ArX.

[pic]

Any halogen compound that contains a benzene ring is not classified as aryl

halide. e.g. Benzyl chloride is not an aryl halide but is a substituted

alkyl halide.

STEP 3: Nomenclature of Aryl Halides (15 minutes).

• Functional group suffix = -halobenzene

Functional group prefix = halo-

Numbering of the ring begins at the halogen-substituted carbon and

proceeds in the direction of the next substituted carbon that possesses

the lower number.

• Mono-substituted aryl halides are characterized using the prefix ortho (o-

), meta (m-) or para (p-) depending on the placement of the substituent

from the halogen or the halogen from a higher priority functional group:

1,2-, 1,3- or 1,4- respectively.

| | | |

|1-chloro-2-ethylbenze|1-chloro-3-ethylbenze|1-chloro-4-ethylbenze|

|ne |ne |ne |

|or |or |or |

|o-ethylchlorobenzene |m-ethylchlorobenzene |p-ethylchlorobenzene |

STEP 4: Chemical Structure of Aryl Halides (15 minutes).

• An aryl halide is classified by its distinct bonding of a halogen

directly to a benzene ring.

o From a structural standpoint, one of the more important things to

realize is the trend in bond lengths of the four aryl halides.

• Since the trend for atomic size goes F < Cl < Br < I, (meaning fluorine

is smaller than chlorine, which is smaller than bromine, etc.) it's

probably not surprising that in terms of bond length, the observation is

as follows:

|[pic] |

|Bond lengths (given in picometers) of the four |

|aryl halides |

• The bond lengths here are measured in picometers, which is a small unit

of measurement used because we are talking about chemical bonds on a

microscopic scale.

• Notice that as we go from fluorine, to chlorine, to bromine, to iodine,

the bond lengths get longer and longer.

• That is because as the size of the halogen gets bigger, the bond has to

elongate to make room for the larger atom that's bonded to the benzene

ring.

STEP 5: Chemical Properties of Aryl Halides (20 minutes).

|Activity: Buzzing (5minutes) |

| |

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

|minutes. |

| |

|What are the chemical properties of Aryl Halides? |

| |

|ALLOW pairs to respond on the question |

| |

|WRITE their response on the flip chart/board |

| |

|CLARIFY and SUMMARIZE by using the content below |

Reactivity of Aryl halides

• In haloalkane, the carbon atom attached to halogen is sp3 hybridised

while in case of haloarene, the carbon atom attached to halogen is sp2-

hybridised.

[pic]

• The sp2 hybridized carbon with a greater s-character is

more electronegative and can hold the electron pair of C—X bond more

tightly than sp3 -hybridized carbon in haloalkane with less s-

character.

• Thus, C—X bond length in halo alkane is shorter than those present

in haloarene.

• Since it is difficult to break a shorter bond than a longer bond,

therefore, haloarenes are less reactive than haloalkanes towards

nucleophilic substitution reaction.

• Unlike alkyl halides, aryl halides are less reactive towards

Nucleophilic substitution reactions, this can be attributed to their

electron release via resonance

[pic]

• Structures III, IV and V stabilise chlorobenzene molecule and give a

double bond character to the carbon-chlorine bond.

• Now because of this the carbon-chlorine bond has more strength and hence

aryl halides are more stable towards Nucleophilic substitution reactions.

• In Alkyl halides the carbon atom attached to halogen is sp3 hybridized

and in aryl halides it is sp2, hybridized, as sp2 hybridized carbon is

more electronegative it does not permit the chlorine atom to get

displaced with the bonded pair of electrons.

Nucleophilic Substitution Reactions of Aryl Halides

• Aryl halides undergo Nucleophilic substitution reactions when a strong

Electron withdrawing group is present on the benzene ring.

• Electron withdrawing groups activate the benzene ring towards

nucleophilic substitution in aryl halides whereas Electron donating

groups deactivate the ring.

Elimination – Addition Mechanism

• In the absence of an electron withdrawing group, nucleophilic

substitution takes place in presence of very strong bases, but the

mechanism is entirely different from what we have seen in bimolecular

nucleophilic substitution reactions.

• This reaction proceeds by a mechanism called benzyne mechanism.

STEP 6: Chemical Reactions involving Aryl Halides (45 minutes).

|Activity: Small Group Discussion (20 minutes) |

| |

|DIVIDE students into small groups. |

| |

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

|What are the chemical reactions involving Aryl Halides? |

| |

|[pic]REFER Students to Book |

| |

|ALLOW students to discuss for 15 minutes. |

| |

|ALLOW each group to present for 5 minutes. |

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|CLARIFY and SUMMARIZE by using the contents below |

Preparations of Aryl Halides

|Halogenation of |[pic] |

|arenes | |

|Via Aryl Diazonium |[pic] |

|salts | |

Electrophilic Aromatic Substitution of Aryl Halides

• Aryl halides are themselves reactive towards electrophilic aromatic

substitution but they are less reactive than benzene.

• This is because halides are weak deactivators.

• Halides direct subsequent reactions ortho, para.

• This makes them a little unusual (activators are usually ortho, para-

directing, deactivators meta-directing).

• The weak deactivation is due to the electronegativity of the halogen

making the intermediate cations less stable than those produced when

benzene undergoes substitution:

[pic]

• The directing effect is due to the resonance stabilisation of the

cationic intermediates derived by ortho or para attack but not by meta

attack. For example, the stabilisation during ortho attack is shown

below:

[pic]

• However, aryl halides can undergo many of the same electrophilic aromatic

substitution reactions that benzene can (review) including nitration,

sulfonation, further halogenation and Friedel-Crafts alkylation or

acylation reactions.

• The following are Electrophilic Aromatic Substitution of aryl halides;

o Halogenation of Aryl halides

[pic]

o Nitration of Aryl halides

[pic]

o Sulphonation of Aryl halides

[pic]

o Friedel-Crafts reaction for Aryl halides

▪ Friedel–Crafts reaction involves the alkylation of

an aromatic ring with an alkyl halide using a strong Lewis

acid catalyst.

▪ With anhydrous ferric chloride as a catalyst, the alkyl

group attaches at the former site of the chloride ion.

[pic]

Addition-Elimination Mechanism

• The generally accepted mechanism for nucleophilic aromatic substitution

in nitro-substituted aryl halides is shown by example below:

[pic]

• Attack of the strong nucleophile on the halogen substituted aromatic

carbon forming an anionic intermediate.

• Loss of the leaving group, the halide ion restores the aromaticity.

• Kinetics of the reaction are observed to be second order.

• The addition step is the rate determining step (loss of aromaticity).

• Nucleophilic substitution, and therefore reaction rate, is facilitated by

the presence of a strong electron withdrawing group (esp. NO2) ortho or

para to the site of substitution, which stabilize the cyclohexadienyl

anion through resonance.

[pic]

• Aryl halide reactivity : -F > -Cl > -Br > -I (note the contrast to

simple nucleophilic substitution)

• The more electronegative the group the greater the ability to attract

electrons which increases the rate of formation of the cyclohexadienyl

anion.

[pic]

Elimination-Addition Mechanism:

• This pathway is followed when the nucleophile is an exceptionally strong

base (e.g. amide ion, NH2-) and the absence of the strong electron

withdrawing groups:

[pic]

• Nucleophilic substitution can lead to substitution on either

o the same carbon that bore the leaving group (see addition mechanism

above) or on an adjacent carbon (see addition mechanism below)

[pic]

• This is most readily apparent when the benzyne is substituted:

[pic]

Aryl Grignards

Aryl Grignards are formed by the reaction of aryl halides (X= Cl, Br or I)

with magnesium metal

[pic]

• Typical solvents are normally anhydrous diethyl ether or tetrahydrofuran.

• Halide reactivity: I > Br > Cl

• Organolithium reagents can also be made.

• Aryl Grignard reactions allow for the introduction of C substituents

other than via Friedel-Crafts alkylation or acylation reactions.

Reaction of Haloarenes With Metals

• Wurtz-Fittig reaction

o The Wurtz–Fittig reaction is the chemical reaction of aryl halides

with alkyl halides and sodium metal in the presence of dry ether to

give substituted aromatic compounds

[pic]

• Fittig reaction.

o Fittig reaction is a chemical reaction of two Aryl halide and

sodium metal in presence of dry ether to give biphenyl as the

product.

[pic]

STEP 7: Key Points (05 minutes).

• Aryl halides are the compounds that contain halogen atom directly

attached to the benzene ring.

• Aryl halides undergo Nucleophilic substitution reactions when a strong

Electron withdrawing group is present on the benzene ring

• The Nucleophilic substitution of Aryl halides is facilitated by the

presence of a strong electron withdrawing group (esp. NO2) ortho or

para to the site of substitution, which stabilize the cyclohexadienyl

anion through resonance

STEP 8: Evaluation (05 minutes).

• What are aryl halides?

• Draw chemical structure of aryl halides

• List chemical properties of aryl halides

• List three chemical reactions under electrophilic aromatic substitution

of Aryl Halides

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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