Pharmaceutical Chemistry Lecture 4 PDF

PL1001 Pharmaceutical Chemistry CHEMISTRY OF AROMATIC COMPOUNDS Lecture 4 Dr Alberto Di Salvo Lecture 4 - content Theory of basicity Phenol and substituted phenols Synthesis of Aspirin Theory of basicity A base can be classified as either a Brönsted Base or a Lewis...

PL1001 Pharmaceutical Chemistry CHEMISTRY OF AROMATIC COMPOUNDS Lecture 4 Dr Alberto Di Salvo Lecture 4 - content Theory of basicity Phenol and substituted phenols Synthesis of Aspirin Theory of basicity A base can be classified as either a Brönsted Base or a Lewis Base. A Brönsted base is a proton acceptor: NaOH + HCl → NaCl + H2O In this reaction -OH ion acts as the base and accepts a proton from the acid. HO- + H+ → H 2O The -OH may also be viewed as an electron pair donor as it donates a pair of electrons to the electron deficient proton (H+). In this capacity the base is acting as a Lewis base or an electron pair donor. Theory of basicity Ammonia (NH3) and related compounds (amines) act as bases in a slightly different way to NaOH. When ammonia reacts with a (mineral) acid, water is not formed, A SALT is formed INSTEAD. NH3 + HCl → NH4+Cl- However ammonia is still acting as a proton acceptor and an electron pair donor. Amines behave in a similar way. In water, the basicity of the amine will affect the strength of the ion pair (salt-like properties for primary amines), therefore the extent of its dissociation RNH2 + H2O ↔ RNH3+ + OH- base conjugate acid Theory of basicity The extent of dissociation can be measured by the pKb scale. CH3NH2 + H2O ↔ CH3NH3+ + HO- base conjugate acid Kb = [ CH3NH3+] [HO-] [CH3NH2] And pKb = - Log10 Kb More recently though, to avoid confusing pKa with pKb values, it is more common to define basicity in terms of pKa according to the following equation. As pKa + pKb = 14 Theory of basicity The differences in pKa and pKb can be illustrated by the following equations CH3NH2 + H2O ↔ CH3NH3+ + HO- Kb = 4.4 x 10-4 pKb = 3.36 base conjugate acid CH3NH3+ ↔ CH3NH2 + H+ Ka = 2.3 x 10-11 pKa = 10.64 Therefore instead of measuring directly the strength of a base, it is now more common to measure the acidity of its conjugate acid (the ammonium ion). i.e. the ability of the conjugate acid to hold onto the proton is a direct measure of the strength of the base. Theory of basicity - application A drug’s pKa value is critical when determining properties such as water solubility. Aspirin is a weak acid (pKa 3.5) and so is fully dissociated at pH 7.4. Therefore it can’t diffuse easily across the cell membrane Morphine on the other hand is a weak base (pKa 7.9) and is partially ionised at pH 7.4. Its ability to cross the cell membrane is less restricted. Phenols Phenols are compounds of the general formula ArOH, where Ar is phenyl or substituted phenyl. HO OH phenol alcohol Phenols differ from alcohols in having the -OH group attached directly to an aromatic ring. Phenols: nomenclature Phenols are generally named as derivatives of the simplest member of the family, phenol (I). Sometimes trivial or special names are in use (II). Occasionally phenols are named as hydroxy- compounds (III). OH OH COOH OH Cl NO2 CH3 o-chlorophenol m-cresol OH NO2 I p-hydroxybenxoic acid 2,4-dinitrophenol II III IV Numbering is often used to denote the relative position(s) of the substituent(s) (IV). Phenols: physical properties The simplest phenols are liquids or low-melting solids. Because of hydrogen bonding, phenols have rather high boiling points (e.g. boiling point of m-cresol is 201oC). Phenol itself is somewhat soluble in water (9g per 100g of water) because of hydrogen bonding with water. Most other phenols are insoluble in water. Generally phenols are colourless. However, they are easily oxidised to form coloured substances. Phenols are acidic in nature (most phenols have Ka values of about 10-10 i.e. pKa ~ 10). Nitro-phenols: physical properties OH OH OH NO2 NO2 I II NO2 III _________________________________________________ B.p., oC Solubility, at 70 mm Hg g / 100 g H2O _________________________________________________ Ortho-Nitrophenol (I) 100 0.2 Meta-Nitrophenol (II) 194 1.35 Para-Nitrophenol (III) Decompose 1.69 Nitro-phenols: physical properties Meta- and para-nitrophenols have very high boiling points because of intermolecular hydrogen bonding (I). H H O O O O H H N O O H H O N N O O O O H II I Meta- and para-nitrophenols are soluble in water due to hydrogen bonding with water molecules (II). Nitro-phenols: physical properties In ortho-nitrophenol -NO2 and -OH groups are located in a favourable relative position for the formation of a hydrogen bond within a single o-nitrophenol molecule (intramolecular hydrogen bonding). H O O N O This intramolecular hydrogen bonding takes the place of intermolecular hydrogen bonding with other phenol molecules or water molecules. Nitro-phenols: physical properties As a consequence, o-nitrophenol has lower boiling point than m- and p-nitrophenols, H H O O O O N H H H O O O N O O H H O N N O O O H O and very poor solubility in water compared to that of m- and p-nitrophenols. Acidity of phenols Phenols are fairly acidic compounds. Aqueous hydroxides (e.g. NaOH) convert phenols into their salts (but not by aq. bicarbonates) ArOH + NaOH → ArO-Na+ + H2O Aqueous mineral acids, carboxylic acids or carbonic acid convert the salts back into free phenols. ArO-Na+ + H2CO3 → ArOH + NaHCO3 Acidity of phenols Phenols are considerably more acidic than alcohols. For example, the pKa of phenol is 9.95, but that of cyclohexanol is about 17. Thus phenol is approximately 107 times more acidic than an alcohol of similar size or shape. H H O O pKa 10 17 The acidity of phenol (compared to cyclohexanol) is increased by resonance stabilisation of its conjugate base. Acidity of phenols What is the source of the enhanced stability? The phenolate anion is stabilised by resonance:..O.... -..-.O...O....O.... -....- Resonance structures cannot be drawn for alkoxide anions:..O.... - Acidity of phenols Because phenoxide anions are stabilised by resonance effects, less energy is required to form phenoxides from phenols than is to form alkoxides from alcohols. Because pKa is directly proportional to the standard free energy of ionisation, phenols have lower pKa values, and are thus more acidic, than alcohols. Reactions of phenols Salicylic acid, the precursor in the synthesis of aspirin, is a good analgesic, but causes gastric bleeding due to the free phenolic group. This is overcome by masking the phenol group as an ester (by reaction with acetic anhydride). The ester is later hydrolysed in vivo to yield the active drug (salicylic acid). O O CO2H CO2H O OH O O CH3 Salicylic acid Aspirin Note that aspirin is a drug itself with anti-inflammatory action.