NTA Level 5 • Semester 1 • PST05106

Chemical Reactions of Heterocyclic Compounds

Pharmaceutical Organic Chemistry • Source Session/Topic 24

Full source-text version: all educational wording from the extracted learning source is retained; only presenter/tutor metadata and web-layout noise are removed, while formatting is improved for readability.

Session 24: Chemical Reactions of Heterocyclic Compounds.

Total Session Time: 120 minutes

Prerequisites

None

Learning Tasks

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

• List chemical properties of heterocyclic compounds

• Explain chemical reactions of heterocyclic compounds

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: Chemical Properties of Heterocyclic Compounds (35 minutes).

|Activity: Brainstorming (5 minutes) |

| |

|Ask students to brainstorm on the following question: |

| |

|What are the chemical properties of heterocyclic compounds? |

| |

|ALLOW few students to respond. |

| |

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

| |

|CLARIFY and SUMMARISE by using the table below |

|Chemical Name |Chemical properties |

|2-AMINOPYRIDINE |The substance decomposes on burning |

| |producing toxic gases and vapours |

| |including nitrous oxides |

| |Reacts with strong oxidants causing |

| |fire and explosion hazard |

| |The substance is a strong base that |

| |is soluble in water |

|3,6-DICHLOROPICOLINIC ACID |The substance decomposes on burning |

| |producing toxic and corrosive gases |

| |Reacts with bases forming salts |

| |Solutions of them are corrosive to |

| |aluminum, iron, and tin |

|2-MERCAPTOBENZOTHIAZOLE |On combustion, forms toxic gases |

| |(carbon monoxide and sulphur |

| |compounds) |

| |The substance decomposes on heating |

| |and on burning producing toxic and |

| |irritating fumes (sulphur and |

| |nitrogen oxides) |

| |Reacts with acids with the formation |

| |of highly toxic fumes of sulphur |

| |compounds |

| |Reacts with acids or acid fumes |

| |producing toxic fumes (sulphur |

| |compounds) |

|2-MERCAPTOBENZOTHIAZOLE |On combustion, forms toxic gases: |

|DISULPHIDE |carbon, sulphur and nitrogen oxides |

| |Reacts with strong oxidants and acids|

| |The substance decomposes on heating |

|2-METHYLPYRIDINE |producing toxic fumes (nitrogen |

| |oxides) |

| |Reacts with oxidants and strong acids|

| | |

| |Attacks copper and its alloys |

|3-METHYLPYRIDINE |The substance decomposes on heating |

| |producing toxic fumes (nitrogen |

| |oxides) |

| |Reacts with oxidants and strong acids|

|4-METHYLPYRIDINE |The substance decomposes on heating |

| |producing toxic fumes (nitrogen |

| |oxides) |

| |Reacts with oxidants and strong acids|

|1-METHYL-2-PYRROLIDONE |The substance decomposes on heating |

| |above 315 °C producing toxic fumes |

| |Reacts with strong acids |

| |Attacks aluminium |

|MORPHOLINE |The substance decomposes on heating |

| |producing toxic fumes (nitrogen |

| |oxides) |

| |The substance is a weak base |

| |Reacts with strong oxidants causing |

| |fire hazard |

| |Attacks copper and its compounds |

|PHENOTHIAZINE |The substance decomposes on heating |

| |and on burning producing toxic and |

| |irritating fumes including nitrogen |

| |oxides and sulphur oxides |

|PHENYLENEPYRENE |Upon heating, toxic fumes are formed |

|PIPERIDINE |The substance decomposes on heating |

| |and on burning producing toxic gases |

| |such as nitrogen oxides |

| |The substance is a medium strong base|

| | |

| |Reacts violently with oxidants |

|PYRIDINE |On combustion, forms toxic fumes |

| |(amines) |

| |The substance decomposes on heating |

| |or on burning producing toxic fumes |

| |(nitrogen oxides and hydrogen |

| |cyanide) |

| |Reacts violently with strong oxidants|

| |and strong acids |

|2-PYRROLIDINONE |The substance decomposes on heating |

| |producing toxic fumes |

| |Reacts with strong acids cf |

| |• methylpyrrolidone Attacks aluminium|

|QUINOLINE |The substance decomposes on heating |

| |and on burning producing toxic fumes |

| |of nitrogen oxides |

| |Reacts with strong oxidants and |

| |maleine anhydride |

|TETRAHYDROTHIOPHENE |On combustion, forms toxic fumes |

| |• Reacts violently with strong |

| |oxidants and nitric acid • Attacks |

| |rubber |

|THIOPHENE |The substance decomposes on heating |

| |and on burning producing toxic and |

| |irritating fumes (sulphur oxides) |

| |• Reacts violently with oxidizing |

| |materials, including fuming nitric |

| |acid |

STEP 3: Chemical Reactions involving Heterocyclic Compounds (60 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 heterocyclic compounds? |

| |

|[pic]REFER Students to Book |

| |

|ALLOW students to discuss for 15 minutes |

| |

|ALLOW each group to present for 5 minutes |

| |

|CLARIFY and SUMMARIZE by using the contents below |

Three-Membered Rings

• Oxiranes (epoxides) are the most commonly encountered three-membered

heterocycles. Epoxides are easily prepared by reaction of alkenes with

peracids, usually with good stereospecificity.

• Because of the high angle strain of the three-membered ring, epoxides are

more reactive that unstrained ethers.

• Addition reactions proceeding by electrophilic or nucleophilic opening of

the ring constitute the most general reaction class.

• Example 1 in the following diagram shows one such transformation, which

is interesting due to subsequent conversion of the addition intermediate

into the corresponding thiirane.

o The initial ring opening is stereoelectronically directed in a

trans-diaxial fashion, the intermediate relaxing to the

diequatorial conformer before cyclizing to a 1,3-oxathiolane

intermediate.

o Other examples show similar addition reactions to thiiranes and

aziridines.

• The acid-catalyzed additions in examples 2 and 3, illustrate the

influence of substituents on the regioselectivity of addition.

• Example 2 reflects the SN2 character of nucleophile (chloride anion)

attack on the protonated aziridine (the less substituted carbon is the

site of addition).

o The phenyl substituent in example 3 serves to stabilize the

developing carbocation to such a degree that SN1 selectivity is

realized.

o The reduction of thiiranes to alkenes by reaction with phosphite

esters (example 6) is highly stereospecific and is believed to take

place by an initial bonding of phosphorous to sulfur.

[pic]

Four-Membered Rings

• Reactions of four-membered heterocycles also show the influence of ring

strain.

• Some examples are given in the following diagram.

• Acid-catalysis is a common feature of many ring-opening reactions, as

shown by examples 1, 2 & 3a.

• In the thietane reaction (2), the sulfur undergoes electrophilic

chlorination to form a chlorosulfonium intermediate followed by a ring-

opening chloride ion substitution.

• Strong nucleophiles will also open the strained ether, as shown by

reaction 3b.

• Cleavage reactions of β-lactones may take place either by acid-catalyzed

acyl exchange, as in 4a, or by alkyl-O rupture by nucleophiles, as in 4b.

• Example 5 is an interesting case of intramolecular rearrangement to an

ortho-ester.

• Finally, the β-lactam cleavage of penicillin G (reaction 6) testifies to

the enhanced acylating reactivity of this fused ring system.

• Most amides are extremely unreactive acylation reagents, thanks to

stabilization by p-π resonance.

• Such electron pair delocalization is diminished in the penicillins,

leaving the nitrogen with a pyramidal configuration and the carbonyl

function more reactive toward nucleophiles.

[pic]

Five-Membered Rings

The chemical reactivity of the saturated members of this class of

heterocycles: tetrahydrofuran, thiolane and pyrrolidine, resemble that of

acyclic ethers, sulfides, and 2º-amines, and will not be described here.

• 1,3-Dioxolanes and dithiolanes are cyclic acetals and thioacetals.

• These units are commonly used as protective groups for aldehydes and

ketones, and may be hydrolyzed by the action of aqueous acid.

It is the "aromatic" unsaturated compounds, furan, thiophene and pyrrole

that require our attention.

• In each case the heteroatom has at least one pair of non-bonding

electrons that may combine with the four π-electrons of the double bonds

to produce an annulene having an aromatic sextet of electrons.

• This is illustrated by the resonance description at the top of the

following diagram.

• The heteroatom Y becomes sp2-hybridized and acquires a positive charge as

its electron pair is delocalized around the ring.

• An easily observed consequence of this delocalization is a change in

dipole moment compared with the analogous saturated heterocycles, which

all have strong dipoles with the heteroatom at the negative end.

• As expected, the aromatic heterocycles have much smaller dipole moments,

or in the case of pyrrole a large dipole in the opposite direction.

• An important characteristic of aromaticity is enhanced thermodynamic

stability, and this is usually demonstrated by relative heats of

hydrogenation or heats of combustion measurements.

• By this standard, the three aromatic heterocycles under examination are

stabilized, but to a lesser degree than benzene.

Additional evidence for the aromatic character of pyrrole is found in its

exceptionally weak basicity (pKa ca. 0) and strong acidity (pKa = 15) for

a 2º-amine.

• The corresponding values for the saturated amine pyrrolidine are:

basicity 11.2 and acidity 32.

[pic]

Electrophilic Substitution of Pyridine

Pyridine is a modest base (pKa=5.2).

• Since the basic unshared electron pair is not part of the aromatic

sextet, as in pyrrole, pyridinium species produced by N-substitution

retain the aromaticity of pyridine.

• As shown below, N-alkylation and N-acylation products may be prepared as

stable crystalline solids in the absence of water or other reactive

nucleophiles.

• The N-acyl salts may serve as acyl transfer agents for the preparation of

esters and amides. Because of the stability of the pyridinium cation, it

has been used as a moderating component in complexes with a number of

reactive inorganic compounds.

• Several examples of these stable and easily handled reagents are shown at

the bottom of the diagram.

• The poly(hydrogen fluoride) salt is a convenient source of HF for

addition to alkenes and conversion of alcohols to alkyl fluorides,

pyridinium chlorochromate (PCC) and its related dichromate analog are

versatile oxidation agents and the tribromide salt is a convenient source

of bromine.

• Similarly, the reactive compounds sulfur trioxide and diborane are

conveniently and safely handled as pyridine complexes.

Amine oxide derivatives of 3º-amines and pyridine are readily prepared by

oxidation with peracids or peroxides, as shown by the upper right

equation.

• Reduction back to the amine can usually be achieved by treatment with

zinc (or other reactive metals) in dilute acid.

[pic]

Other Reactions of Pyridine

• Thanks to the nitrogen in the ring, pyridine compounds undergo

nucleophilic substitution reactions more easily than equivalent benzene

derivatives.

• In the following diagram, reaction 1 illustrates displacement of a 2-

chloro substituent by ethoxide anion.

• The addition-elimination mechanism shown for this reaction is helped by

nitrogen's ability to support a negative charge.

• A similar intermediate may be written for substitution of a 4-

halopyridine, but substitution at the 3-position is prohibited by the the

failure to create an intermediate of this kind.

• The two Chichibabin aminations in reactions 2 and 3 are remarkable in

that the leaving anion is hydride (or an equivalent). Hydrogen is often

evolved in the course of these reactions.

• In accord with this mechanism, quinoline is aminated at both C-2 and C-4.

Addition of strong nucleophiles to N-oxide derivatives of pyridine

proceed more rapidly than to pyridine itself, as demonstrated by

reactions 4 and 5.

• The dihydro-pyridine intermediate easily loses water or its equivalent by

elimination of the –OM substituent on nitrogen.

[pic]

STEP 4: Key Points (10 minutes)

• Chemical properties of heterocyclic compounds are variable depending

on the class of the compound.

• Chemical reactions of heterocyclic compounds depend on the class of

the heterocyclic compound.

STEP 5: Evaluation (10 minutes)

• List chemical properties of heterocyclic compounds.

• List chemical reactions of heterocyclic compounds.

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.

Rama Rao Nadendla (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

← Previous Topic Next Topic →View all Pharmaceutical Organic Chemistry topics Open Complete Full Notes

PDF / OFFLINE NOTES

Unataka kutumiwa notes hizi kupitia WhatsApp?Kwa notes zilizopangiliwa vizuri kwa kusoma offline au PDF, bonyeza kitufe hapa chini. Ujumbe wenye Level, Semester, Module na Topic utaandaliwa moja kwa moja.TUMIWA NOTES WHATSAPP

WhatsApp: 255620339260