Chemistry of Dyes and Drugs BCH6T16

Syllabus topics (RTMNU)

• Introduction
• Classification of Dyes on the basis of chemical structure (constitution) and method of applications on fibres
• Relation of colour to resonance in the following classes of dyes: Azo, Triphenylmethane, Anthraquinone
• Otto Witt's theory (electronic concept) and valence bond theory (modern electronic concept) of dyes
• Absorption of visible light, colour of wavelength absorbed and complementary colour
• Chromogen, chromophore, auxochrome, bathochromic and hypsochromic shifts

Introduction to dyes

Dye: A dye is a coloured organic compound that can be fixed firmly on a material (fibre, paper, leather, food) so that the colour does not wash out easily. Every coloured substance is not a dye: a dye must (1) have a suitable colour, (2) be soluble (or made soluble) during dyeing, and (3) have groups that attach it to the fibre (fastness to light, washing and rubbing).

Pigment vs dye: a pigment is insoluble and is held on the surface by a binder (paints); a dye penetrates and binds to the fibre.

Classification of dyes on the basis of chemical structure (constitution)

Classification on the basis of method of application on fibres

1. Acid dyes: contain –SO₃H or –COOH; applied from acidic bath to wool, silk, nylon (protein –NH₃⁺ groups bind the dye anion). Ex: Orange II, Congo red (on wool).
2. Basic (cationic) dyes: contain –NH₂/–NR₂ as salts; dye wool, silk, acrylic directly; cotton only with a mordant (tannic acid). Ex: Malachite green, Crystal violet, Methylene blue.
3. Direct (substantive) dyes: dye cotton directly from a neutral/alkaline bath with salt; long, flat molecules held by H-bonds. Ex: Congo red.
4. Mordant dyes: need a metal salt (Al, Cr, Fe, Sn) called mordant, which forms an insoluble coloured complex (lake) on the fibre. Ex: Alizarin (red with Al, violet-black with Fe).
5. Vat dyes: insoluble; reduced in alkali (sodium hydrosulphite, Na₂S₂O₄) to a soluble leuco form, absorbed by fibre, then air-oxidised back to the insoluble dye inside the fibre. Very fast. Ex: Indigo.
6. Disperse dyes: sparingly soluble, used as fine dispersions for polyester, acetate.
7. Reactive dyes: form a covalent bond with –OH of cellulose (e.g. via chlorotriazine group); excellent wash fastness.
8. Azoic (ingrain) dyes: the azo dye is produced inside the fibre by coupling (fibre soaked in naphthol, then dipped in a diazonium salt).
9. Sulphur dyes: applied from Na₂S solution, cheap dark shades on cotton.

Absorption of visible light and complementary colour

White light (about 400–750 nm) contains all colours. When a compound absorbs light of a certain wavelength, we see the remaining light, i.e. the complementary colour of the absorbed one.

A compound absorbing only in the UV (below 400 nm) looks colourless. Extending conjugation lowers the energy gap (ΔE = hc/λ), so absorption moves into the visible region and the compound becomes coloured.

Otto Witt's theory (1876) — chromophore, chromogen and auxochrome

• Chromophore: an unsaturated group responsible for colour. Ex: –N=N– (azo), –N=O (nitroso), –NO₂ (nitro), >C=O (carbonyl), >C=C< in conjugation, quinonoid ring.
• Chromogen: an aromatic compound containing a chromophore; it may be coloured but is not yet a dye. Ex: azobenzene (orange-red) is a chromogen.
• Auxochrome: a group which by itself does not give colour but, when attached to a chromogen, deepens the colour and makes the compound a dye by giving it a salt-forming (acidic or basic) character that binds the fibre. Ex: –OH, –NH₂, –NHR, –NR₂, –COOH. (–SO₃H mainly increases water solubility.)

Example: azobenzene (chromogen) + –NH₂ (auxochrome) → p-aminoazobenzene (aniline yellow), a dye.

Limitations of Witt's theory: it is empirical; it does not explain why these groups give colour or predict the exact colour.

Bathochromic and hypsochromic shifts

• Bathochromic shift (red shift): absorption moves to a longer wavelength; colour "deepens" (yellow → orange → red → violet → blue). Caused by auxochromes and extended conjugation.
• Hypsochromic shift (blue shift): absorption moves to a shorter wavelength; colour becomes lighter. Caused by removing conjugation or by protonating an auxochrome lone pair (e.g. –NH₂ → –NH₃⁺).
• Related terms: hyperchromic (intensity increases) and hypochromic (intensity decreases).

Valence bond (modern electronic) theory and relation of colour to resonance

According to the valence bond theory, colour arises because the dye molecule is a resonance hybrid of several structures (often charged, with quinonoid forms). The more effective the resonance (more contributing structures, longer conjugated path, electron donor at one end and acceptor at the other), the smaller the energy difference between ground and excited states, and the longer the wavelength absorbed. Auxochromes act because their lone pair enters resonance with the chromophore.

(a) Azo dyes: In p-aminoazobenzene and methyl orange the –NMe₂ lone pair is pushed through the ring and the –N=N– group, giving a dipolar quinonoid structure (Me₂N⁺=C₆H₄=N–N^––Ar). In acid solution methyl orange is protonated on the azo nitrogen and the positive charge is shared between the azo N and the –NMe₂ N through a quinonoid ring — this extended resonance gives the red acid form; in alkali the less delocalised benzenoid azo form is yellow.

(b) Triphenylmethane dyes: In malachite green the positive charge is delocalised over the central carbon and two –NMe₂ groups via two equivalent quinonoid structures of equal energy. Equivalent resonance structures give very strong absorption, so the dye is intensely green. Crystal violet has three –NMe₂ groups, more resonance, and is violet. The colourless leuco base (sp³ central carbon) has no such resonance.

(c) Anthraquinone dyes: Anthraquinone itself is pale yellow (two C=O groups cross-conjugated). Electron-donating –OH or –NH₂ groups at positions 1 and 2 set up donor→acceptor resonance with the C=O groups (and intramolecular H-bonding at position 1), shifting absorption to longer wavelength; alizarin (1,2-dihydroxy) is orange-red, and its metal lakes are red to violet.

Likely exam questions

1. (Long, 8 marks) Explain Otto Witt's theory of colour and constitution. Define chromophore, chromogen and auxochrome with suitable examples.
2. (Long, 8 marks) Classify dyes on the basis of method of application. Explain the relation of colour to resonance in azo and triphenylmethane dyes.
3. (Short, 4 marks) What are bathochromic and hypsochromic shifts?
4. (Short, 4 marks) Explain complementary colour with a table of absorbed and observed colours.
5. (Short, 4 marks) What are vat dyes? Give one example.

Syllabus topics (RTMNU)

• Synthesis and uses of following selected dyes: (i) Methyl Orange
• (ii) Eriochrome Black T
• (iii) Congo Red
• (iv) Malachite Green
• (v) Methylene Blue
• (vi) Alizarin
• (vii) Indigo
• (viii) Crystal violet
• (ix) Phenolphthalein
• (x) Fluorescein

Most dyes in this unit are made by one of four routes: (1) diazotisation and coupling (azo dyes), (2) condensation with an aldehyde/ketone followed by oxidation (triphenylmethane dyes), (3) condensation of phthalic anhydride with phenols (phthaleins), (4) special routes for anthraquinone, indigo and thiazine dyes.

(i) Methyl orange

Synthesis: Sulphanilic acid is dissolved in Na₂CO₃ solution, NaNO₂ is added and the mixture is poured into ice-cold HCl → diazotised sulphanilic acid. This is coupled with N,N-dimethylaniline (in dilute acid) at the para position → red acid form (helianthin); NaOH gives the orange sodium salt, methyl orange.

HO₃S–C₆H₄–N₂⁺ + C₆H₅NMe₂ → HO₃S–C₆H₄–N=N–C₆H₄–NMe₂ (p) → (NaOH) sodium salt

Uses: acid–base indicator (red below pH 3.1, yellow above 4.4) for strong acid–weak base titrations; acid dye for wool.

(ii) Eriochrome Black T

An o,o′-dihydroxy azo dye (sodium 1-(1-hydroxy-2-naphthylazo)-6-nitro-2-naphthol-4-sulphonate).

Synthesis: 1-Amino-2-naphthol-4-sulphonic acid is nitrated to its 6-nitro derivative, which is diazotised (NaNO₂/acid, cold) and coupled with 1-naphthol (α-naphthol) in alkaline medium at the 2-position → Eriochrome Black T.

Uses: metal-ion indicator in EDTA (complexometric) titrations of Mg²⁺, Ca²⁺, Zn²⁺ at pH 10 — wine-red metal complex turns blue at the end point; used to find hardness of water; mordant dye for wool.

(iii) Congo red

Synthesis: Benzidine (4,4′-diaminobiphenyl) is tetrazotised (both –NH₂ groups diazotised) and coupled with two molecules of naphthionic acid (4-aminonaphthalene-1-sulphonic acid) → Congo red, a bis-azo dye (isolated as the disodium salt).

Uses: first direct dye for cotton (dyes cotton without mordant); indicator (blue below pH 3, red above pH 5); stain for amyloid in histology. Benzidine is carcinogenic, so its use is now restricted.

(iv) Malachite green

Synthesis (triphenylmethane route):

1. Benzaldehyde + 2 molecules of N,N-dimethylaniline, heated with conc. H₂SO₄ (or ZnCl₂) → condensation at the para positions → leuco base (colourless), C₆H₅CH(C₆H₄NMe₂)₂.
2. Oxidation with PbO₂ in acid → carbinol base (colourless) C₆H₅C(OH)(C₆H₄NMe₂)₂.
3. Treatment with HCl → loss of water → quinonoid cation → malachite green (green, as chloride or zinc chloride double salt).

Uses: basic dye for silk, wool, leather, jute; biological stain; formerly antifungal in fish farming (now restricted because of toxicity).

(v) Methylene blue

A thiazine (phenothiazinium) dye.

Synthesis (outline): N,N-dimethylaniline is converted to N,N-dimethyl-p-phenylenediamine (nitrosation with HNO₂, then reduction). This is oxidised (K₂Cr₂O₇) in the presence of sodium thiosulphate to a thiosulphonic acid, which is condensed and oxidised with another molecule of dimethylaniline to an indamine-thiosulphonic acid. Heating (with ZnCl₂/CuSO₄) closes the sulphur-containing ring → methylene blue, isolated as the chloride (or zinc chloride double salt).

Uses: basic dye for cotton (with tannin mordant), paper, silk; biological stain (bacteria, nuclei); redox indicator (blue oxidised, colourless reduced leuco form); medicine for methaemoglobinaemia.

(vi) Alizarin

1,2-Dihydroxyanthraquinone, originally from madder root.

Synthesis: Anthraquinone is sulphonated with fuming H₂SO₄ → anthraquinone-2-sulphonic acid (sodium salt, "silver salt"). Fusion with NaOH and a little KClO₃ (oxidising agent) at about 200 °C replaces –SO₃Na by –ONa and introduces a second –OH at position 1 → sodium alizarate; acidification gives alizarin (orange-red crystals).

Uses: classic mordant dye — red lake with Al³⁺ (Turkey red), violet-black with Fe³⁺, brown with Cr³⁺; pigment; acid–base indicator.

(vii) Indigo

Synthesis (Heumann process):

1. Aniline + chloroacetic acid → N-phenylglycine (C₆H₅NHCH₂COOH).
2. Fusion with sodamide (NaNH₂) or NaOH/KOH at high temperature → indoxyl (cyclisation).
3. Air oxidation of two indoxyl molecules → indigo (blue).

Uses: most famous vat dye; dyes cotton (denim jeans). For dyeing it is reduced with Na₂S₂O₄/NaOH to soluble yellow "indigo white" (leuco form), absorbed by the cloth and re-oxidised by air to blue indigo.

(viii) Crystal violet

Synthesis: N,N-dimethylaniline reacts with phosgene (COCl₂) → Michler's ketone, 4,4′-bis(dimethylamino)benzophenone. Michler's ketone is condensed with a third molecule of dimethylaniline in the presence of POCl₃ → crystal violet (hexamethyl-pararosaniline chloride).

Uses: basic violet dye for silk, wool, paper and inks; main stain in Gram staining of bacteria; antiseptic ("gentian violet").

(ix) Phenolphthalein

Synthesis: Phthalic anhydride + 2 molecules of phenol, heated with conc. H₂SO₄ (or anhydrous ZnCl₂) → condensation at the para positions of phenol with loss of water → phenolphthalein (lactone form, colourless).

Uses: acid–base indicator — colourless below pH 8.2, pink-red above about 10 (in alkali the lactone ring opens to a coloured quinonoid dianion); used in strong acid–strong base and weak acid–strong base titrations; formerly a laxative.

(x) Fluorescein

Synthesis: Phthalic anhydride + 2 molecules of resorcinol, heated with anhydrous ZnCl₂ at about 200 °C → condensation and ring closure (xanthene ring) → fluorescein (red-orange powder).

Uses: its alkaline solution (uranine, the sodium salt) shows intense yellow-green fluorescence; adsorption indicator in argentometric titrations (Fajans method); tracing leaks and underground water; eye examination (fluorescein angiography); its tetrabromo derivative is eosin (red ink).

Likely exam questions

1. (Long, 8 marks) Give the synthesis and uses of methyl orange and Congo red.
2. (Long, 8 marks) Describe the synthesis of malachite green and crystal violet. Why is the leuco base colourless?
3. (Short, 4 marks) How is indigo prepared by the Heumann process? Why is it called a vat dye?
4. (Short, 4 marks) Give the synthesis and uses of fluorescein.
5. (Short, 4 marks) How is alizarin prepared from anthraquinone?

Syllabus topics (RTMNU)

• Definition, history, scope and development of Pharmacognosy
• Definition of drug, ideal properties of drug
• Prodrug, soft drug, hard drug
• Classification of Drugs: Alphabetical, morphological – Doctrine of nature, taxonomical classification of drugs
• Chemical classification of drugs, Pharmacological classification of drugs, Classification of drugs based on therapeutic effects and areas
• Pharmacokinetics: Absorption, distribution, metabolism, interaction, excretion

Introduction to drug chemistry — definition, history and scope of Pharmacognosy

Pharmacognosy (Greek pharmakon = drug, gnosis = knowledge) is the study of drugs of natural origin — plants, animals, minerals and microbes — including their identification, cultivation, collection, chemistry, quality control and uses. The term came into use in the early 19th century (J.A. Schmidt, 1811; C.A. Seydler, 1815).

History (brief): herbal remedies are described in ancient texts — the Indian Charaka Samhita and Sushruta Samhita (Ayurveda), Egyptian papyri, Chinese herbals and Greek writings (Hippocrates; Dioscorides' De Materia Medica). Isolation of pure active compounds began in the 19th century: morphine from opium (Sertürner, early 1800s), quinine from cinchona bark, and later penicillin from a mould (Fleming, 1928). Modern drug chemistry grew from these natural leads to synthetic drugs (aspirin, sulpha drugs, etc.).

Scope / development: discovery of new medicines from plants (e.g. vincristine from Catharanthus roseus, artemisinin from Artemisia annua); standardisation and quality control of herbal drugs; plant tissue culture and biotechnology for drug production; phytochemistry; herbal cosmetics and nutraceuticals; Ayurveda and other traditional systems; search for safer, cheaper medicines.

Definition of drug and ideal properties of a drug

Drug (WHO): any substance or product that is used or intended to be used to modify or explore physiological systems or pathological states for the benefit of the recipient. Simply: a chemical used to diagnose, prevent, treat or cure disease.

Ideal properties of a drug:

1. High efficacy and selectivity — acts on the target (receptor/enzyme/microbe) only.
2. Safe — low toxicity, few side effects, wide therapeutic index.
3. Good bioavailability — absorbed well, preferably orally.
4. Suitable duration of action — convenient dosing.
5. Chemically stable — long shelf life.
6. Does not cause dependence, allergy or drug resistance easily.
7. Predictable metabolism and excretion, few drug interactions.
8. Easy and economical to manufacture; acceptable taste and form.

Prodrug, soft drug and hard drug

• Prodrug: an inactive (or less active) compound that is converted inside the body by enzymes or chemical reaction into the active drug. Used to improve absorption, taste, stability or to target a site. Examples: levodopa → dopamine in the brain (Parkinson's disease); enalapril → enalaprilat; codeine is partly converted to morphine.
• Soft drug: an active drug designed to be quickly metabolised, after doing its job, into inactive and non-toxic products in a predictable single step. This reduces side effects. Example: esmolol (short-acting β-blocker, hydrolysed by blood esterases).
• Hard drug: (in medicinal chemistry) a drug designed so that it is not metabolised and is excreted unchanged, avoiding toxic metabolites. In everyday language "hard drugs" also means strongly addictive narcotics (heroin, cocaine); in this syllabus the medicinal-chemistry meaning is intended.

Classification of drugs

1. Alphabetical: drugs arranged A to Z by common/Latin name (as in pharmacopoeias, dictionaries). Easy to locate, but gives no idea of nature or action.
2. Morphological: crude drugs grouped by the plant part used — leaves (senna, vasaka), barks (cinchona, cinnamon), roots (rauwolfia, ipecac), rhizomes (ginger), seeds (nux vomica), fruits (fennel), flowers (clove), and organised vs unorganised drugs (gums, resins, latex). Useful for identification.
3. Doctrine of nature / doctrine of signatures: an old belief that a plant's shape or colour shows the organ it can cure (e.g. walnut kernel for the brain, red juices for blood). It is of historical interest only and not scientific.
4. Taxonomical: drugs grouped by the botanical family of the source plant — e.g. Solanaceae (belladonna, datura), Apocynaceae (rauwolfia, vinca), Umbelliferae/Apiaceae (fennel, coriander). Shows relationships, but not chemistry or action.
5. Chemical: by the main active constituent — alkaloids (morphine, quinine), glycosides (digoxin, senna), tannins, volatile oils (clove, peppermint), resins, lipids, carbohydrates. Useful for chemists and for quality control.
6. Pharmacological: by the action on the body — analgesics, antipyretics, sedatives/hypnotics, antibiotics, diuretics, cardiotonics, anticoagulants, etc. Most useful to doctors.
7. Therapeutic (by disease/area): antimalarials, antitubercular drugs, anticancer drugs, antidiabetics, antihypertensives, anti-leprosy drugs, anti-HIV drugs, drugs for the central nervous system, cardiovascular system, etc.

Pharmacokinetics — absorption, distribution, metabolism, interaction, excretion

Pharmacokinetics is "what the body does to the drug" — the movement of a drug through the body with time (ADME). (Pharmacodynamics is what the drug does to the body.)

1. Absorption: passage of the drug from the site of administration into the blood. Depends on lipid solubility, ionisation (pK_a and pH), particle size, dosage form, blood flow. Intravenous drugs skip absorption (100% bioavailability). Oral drugs may lose part of the dose by first-pass metabolism in the liver.
2. Distribution: transport by blood to tissues. Affected by plasma protein binding (bound drug is inactive), tissue blood flow, and barriers such as the blood–brain barrier and placenta. Described by the volume of distribution (V_d).
3. Metabolism (biotransformation): chemical change of the drug, mainly in the liver. Phase I — oxidation (cytochrome P450 enzymes), reduction, hydrolysis; Phase II — conjugation with glucuronic acid, sulphate, glycine, acetyl group, making the drug more water-soluble for excretion. Metabolism usually inactivates a drug but activates a prodrug.
4. Drug interaction: one drug changes the effect of another — e.g. enzyme inducers (rifampicin) speed metabolism of other drugs; enzyme inhibitors increase their levels; antacids reduce absorption of tetracycline. Interactions can be additive, synergistic or antagonistic.
5. Excretion: removal of the drug and metabolites, mainly by the kidneys (glomerular filtration, tubular secretion); also bile/faeces, lungs (volatile anaesthetics), sweat, saliva and milk. Half-life (t_½) is the time for plasma concentration to fall to half; it decides the dosing interval.

Likely exam questions

1. (Long, 8 marks) Define drug. Give the ideal properties of a drug and explain the different methods of classification of drugs.
2. (Long, 8 marks) What is pharmacokinetics? Explain absorption, distribution, metabolism and excretion of drugs.
3. (Short, 4 marks) Distinguish between prodrug and soft drug with examples.
4. (Short, 4 marks) Write a note on the scope of Pharmacognosy.
5. (Short, 4 marks) What is the morphological classification of crude drugs?

Syllabus topics (RTMNU)

• Synthesis of the representative drugs of the following classes: analgesic agents, antipyretic agents, anti-inflammatory agents (Aspirin, Paracetamol, Ibuprofen)
• Antibiotics (Chloramphenicol)
• Antibacterial and antifungal agents (Sulphonamides; Sulphamethoxazole, Sulphacetamide, Trimethoprim)
• Antiviral agents (Acyclovir)
• Central Nervous System agents (Phenobarbital, Diazepam)
• Cardiovascular (Glyceryl trinitrate)
• Antileprosy (Dapsone)
• HIV-AIDS related drugs (AZT – Zidovudine)

Analgesic, antipyretic and anti-inflammatory agents

Analgesics relieve pain, antipyretics lower fever and anti-inflammatory drugs reduce swelling. Aspirin and ibuprofen (NSAIDs) do all three by inhibiting cyclo-oxygenase (COX) and prostaglandin synthesis; paracetamol is analgesic and antipyretic but only weakly anti-inflammatory.

Aspirin (acetylsalicylic acid)

1. Phenol → sodium phenoxide (NaOH); CO₂ under pressure at about 125 °C (Kolbe–Schmitt reaction) → sodium salicylate → (H⁺) salicylic acid.
2. Salicylic acid + acetic anhydride, a few drops of conc. H₂SO₄ (or H₃PO₄), warm → aspirin + acetic acid (acetylation of the phenolic –OH).

HO–C₆H₄–COOH + (CH₃CO)₂O → CH₃COO–C₆H₄–COOH + CH₃COOH

Uses: pain, fever, inflammation (arthritis); low dose as antiplatelet to prevent heart attack. Side effect: gastric irritation; avoided in children with viral fever (Reye's syndrome).

Paracetamol (acetaminophen, 4-hydroxyacetanilide)

1. Phenol → nitration (dil. HNO₃) → p-nitrophenol (separated from ortho isomer).
2. Reduction (Fe/HCl or H₂/catalyst) → p-aminophenol.
3. Acetylation with acetic anhydride → paracetamol (the –NH₂ is acetylated, not the –OH, because the amine is more nucleophilic).

Uses: fever and mild to moderate pain; safe for the stomach. Overdose causes liver damage.

Ibuprofen (2-(4-isobutylphenyl)propanoic acid)

BHC "green" process (3 steps):

1. Isobutylbenzene + acetic anhydride, HF catalyst (Friedel–Crafts acylation) → 4-isobutylacetophenone.
2. Catalytic hydrogenation (H₂, Raney Ni) → 1-(4-isobutylphenyl)ethanol.
3. Carbonylation with CO in presence of a palladium catalyst → ibuprofen.

(The older Boots process used 6 steps: acylation → Darzens reaction with ethyl chloroacetate → hydrolysis/decarboxylation to aldehyde → oxime → nitrile → hydrolysis.) The BHC route has high atom economy and little waste. Uses: pain, fever, arthritis, menstrual pain.

Antibiotics — Chloramphenicol

A broad-spectrum antibiotic first isolated from Streptomyces venezuelae; now made synthetically. It has a p-nitrophenyl group, a 1,3-propanediol chain and a dichloroacetamide group; only the D-(–)-threo isomer is active.

Synthesis from p-nitroacetophenone (outline):

1. Bromination → p-nitro-α-bromoacetophenone.
2. Reaction with hexamine, then acid hydrolysis → p-nitro-α-aminoacetophenone.
3. Acetylation of –NH₂ (acetic anhydride) → α-acetamido ketone.
4. Hydroxymethylation with formaldehyde (NaHCO₃) → introduces –CH₂OH.
5. Reduction of C=O with aluminium isopropoxide (Meerwein–Ponndorf–Verley) → diol (threo form).
6. Hydrolysis of the acetyl group, resolution of the racemic amine to the D-(–)-threo isomer.
7. Dichloroacetylation with methyl dichloroacetate → chloramphenicol.

Uses: typhoid, bacterial meningitis, eye infections (eye drops). Serious side effect: bone-marrow depression, "grey baby syndrome" in newborns — so used carefully.

Antibacterial and antifungal agents — Sulphonamides

Sulpha drugs are derivatives of sulphanilamide (p-aminobenzenesulphonamide). They resemble p-aminobenzoic acid (PABA) and block bacterial folic-acid synthesis (bacteriostatic).

Common intermediate: p-acetamidobenzenesulphonyl chloride

Aniline → acetanilide (acetic anhydride; protects –NH₂) → with chlorosulphonic acid (ClSO₃H) → p-acetamidobenzenesulphonyl chloride. With ammonia → p-acetamidobenzenesulphonamide → acid hydrolysis → sulphanilamide.

Sulphamethoxazole

p-Acetamidobenzenesulphonyl chloride + 3-amino-5-methylisoxazole (in pyridine) → N⁴-acetylsulphamethoxazole → hydrolysis of the acetyl group (NaOH or acid) → sulphamethoxazole. Used with trimethoprim (co-trimoxazole) for urinary and respiratory infections.

Sulphacetamide

Sulphanilamide + acetic anhydride → N¹,N⁴-diacetylsulphanilamide → partial alkaline hydrolysis removes the N⁴-acetyl group → sulphacetamide (N¹-acetylsulphanilamide), used as sodium salt in eye drops for conjunctivitis.

Trimethoprim

A 2,4-diaminopyrimidine. Outline: 3,4,5-trimethoxybenzaldehyde is condensed with a 3-alkoxypropionitrile (or 3-anilinopropionitrile) in base to give a benzylidene nitrile, which is cyclised with guanidine → trimethoprim [5-(3,4,5-trimethoxybenzyl)pyrimidine-2,4-diamine]. It inhibits bacterial dihydrofolate reductase, so with a sulphonamide it blocks two steps of folate synthesis (synergy).

Antiviral agent — Acyclovir

An acyclic guanosine analogue (9-[(2-hydroxyethoxy)methyl]guanine).

1. Guanine is acetylated → N²,9-diacetylguanine.
2. Heated with 2-(acetoxymethoxy)ethyl acetate and an acid catalyst (p-toluenesulphonic acid) → alkylation at N-9 with the acyclic side chain.
3. Removal of acetyl groups with aqueous ammonia (or NaOH/methanol) → acyclovir.

Uses: herpes simplex, chickenpox and shingles (varicella-zoster). It is activated by viral thymidine kinase, so it acts selectively on infected cells.

Central nervous system agents — Phenobarbital and Diazepam

Phenobarbital (5-ethyl-5-phenylbarbituric acid)

1. Diethyl phenylmalonate (from ethyl phenylacetate + diethyl oxalate, then heating to lose CO) is ethylated with ethyl bromide and sodium ethoxide → diethyl ethylphenylmalonate.
2. Condensation with urea in presence of sodium ethoxide → ring closure → phenobarbital + 2 C₂H₅OH.

Uses: sedative-hypnotic and anticonvulsant (epilepsy). Habit-forming.

Diazepam (Valium)

1. 2-Amino-5-chlorobenzophenone + chloroacetyl chloride → 2-(chloroacetamido)-5-chlorobenzophenone.
2. Treatment with ammonia → replacement of Cl by NH₂ and cyclisation (amine condenses with C=O) → 7-chloro-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one (nordazepam).
3. N-Methylation (dimethyl sulphate or CH₃I with base) → diazepam.

Uses: anxiety, insomnia, muscle spasm, status epilepticus, alcohol withdrawal. Acts on GABA_A receptors.

Cardiovascular agent — Glyceryl trinitrate

Synthesis: Glycerol is added slowly to a cold mixture of conc. HNO₃ and conc. H₂SO₄, keeping the temperature low → esterification of all three –OH groups → glyceryl trinitrate (nitroglycerin) + 3H₂O.

C₃H₅(OH)₃ + 3HNO₃ → C₃H₅(ONO₂)₃ + 3H₂O

Uses: relief of angina pectoris (sublingual tablet or spray) — it releases nitric oxide, which relaxes blood vessels. (It is also an explosive, so it is handled as a dilute preparation.)

Anti-leprosy agent — Dapsone

4,4′-Diaminodiphenyl sulphone (DDS).

1. p-Chloronitrobenzene + Na₂S → 4,4′-dinitrodiphenyl sulphide.
2. Oxidation (H₂O₂/acetic acid or K₂Cr₂O₇) → 4,4′-dinitrodiphenyl sulphone.
3. Reduction of both –NO₂ groups (Fe/HCl or Sn/HCl) → dapsone.

Uses: leprosy (part of multi-drug therapy with rifampicin and clofazimine), dermatitis herpetiformis; acts like sulphonamides on folate synthesis.

HIV-AIDS related drug — AZT (Zidovudine)

3′-Azido-3′-deoxythymidine, the first approved anti-HIV drug (1987); a nucleoside reverse-transcriptase inhibitor.

1. Thymidine → protection of the 5′-OH with trityl chloride → 5′-O-tritylthymidine.
2. Mesylation of the 3′-OH (methanesulphonyl chloride) and treatment with base → 2,3′-anhydro (cyclo) nucleoside.
3. Ring opening with lithium azide (LiN₃) → 3′-azido group with the correct configuration.
4. Removal of the trityl group with acid → AZT (zidovudine).

Uses: treatment of HIV infection (in combination therapy) and prevention of mother-to-child transmission. In the cell it is phosphorylated to the triphosphate, which stops viral DNA chain growth because it has no 3′-OH.

Likely exam questions

1. (Long, 8 marks) Give the synthesis and uses of aspirin, paracetamol and ibuprofen.
2. (Long, 8 marks) Describe the synthesis of sulphamethoxazole and sulphacetamide. Explain why sulphonamides are combined with trimethoprim.
3. (Short, 4 marks) How is phenobarbital synthesised? Give its uses.
4. (Short, 4 marks) Give the synthesis and use of glyceryl trinitrate.
5. (Short, 4 marks) Write the synthesis of dapsone.