PHA114 Amines 1 Notes PDF

WEEK 19 MPharm Programme PHA114 Amines Dr. Matt Smith Slide 1 MPharm PHA114 Amines 1 WEEK 19 Occurrence of Amines Many biologically significant molecules contain...

WEEK 19 MPharm Programme PHA114 Amines Dr. Matt Smith Slide 1 MPharm PHA114 Amines 1 WEEK 19 Occurrence of Amines Many biologically significant molecules contain amino groups – amino acids – vitamins – DNA bases (A, T, G, C) – RNA bases (A, U, G, C) – alkaloids (e.g., caffeine, nicotine) – drug molecules – physiological molecules ~70% of pharmaceuticals contain nitrogen Slide 2 MPharm PHA114 Amines 1 WEEK 19 Properties of Amines Contain a nitrogen atom with a lone pair of electrons Nitrogen is very electronegative (Group 5); 3.0 – but not quite as electronegative as oxygen (Group 6); 3.5 Results in: – N-H bond being very polar – Hydrogen bonding high boiling points drug-receptor interactions – Amines being organic bases similar to ammonia, a common weak inorganic base – Amines being nucleophilic Slide 3 MPharm PHA114 Amines 1 WEEK 19 Amino Acids -amino acids contain: – a basic amino group, – NH2 – an acidic carboxyl group, –CO2H – a side chain, R Twenty essential amino acids – all are necessary for protein synthesis Humans can synthesise eleven of the twenty (non-essential amino acids) – the other nine obtained from diet (essential amino acids) Differ in side-chain characteristics – H or alkyl – contain an -OH – contain sulfur – contain a non-basic nitrogen – has -COOH – has a basic nitrogen Slide 4 MPharm PHA114 Amines 1 WEEK 19 Nucleosides A, G, C, T are found in DNA A, G, C, U are found in RNA Slide 5 MPharm PHA114 Amines 1 WEEK 19 Alkaloids Alkaloids are natural products that contain one or more nitrogen heteroatoms Many are used as anesthetics, antidepressants and stimulants Slide 6 MPharm PHA114 Amines 1 WEEK 19 Classifying Amines Alkylamines …. alkyl-substituted Arylamines … aryl-substituted Classified: 1° primary (RNH2) 2° secondary (R2NH) 3° tertiary (R3N) (R not necessarily identical) Slide 7 MPharm PHA114 Amines 1 WEEK 19 Quaternary Ammonium Ions A nitrogen atom with four attached groups is positively charged When all substituents R are alkyl / aryl compounds – we produce quaternary ammonium salts Slide 8 MPharm PHA114 Amines 1 WEEK 19 Heterocyclic Amines If the nitrogen atom occurs as part of a ring, the compound is designated as being heterocyclic Each ring system has its own parent name Slide 9 MPharm PHA114 Amines 1 WEEK 19 Structure and Bonding in Amines Bonding to N is similar to that in ammonia – N is sp3-hybridised – Lone pair of electrons in an sp3 orbital – The three groups and the unshared electron pair around nitrogen result in a tetrahedral geometry – If only the location of the groups (and not the unshared electron pair) are considered, the shape of the amine is trigonal pyramidal – C–N–C bond angles are close to 109° tetrahedral value – High electrostatic potential at nitrogen - reactivity of nitrogen lone pair dominates properties of amines (partial negative charge is localised in the region of the nonbonding electrons) Slide 10 MPharm PHA114 Amines 1 WEEK 19 Geometry at N Angle that the C—N bond makes with bisector of H—N—H angle is a measure of geometry at N – this is not the same as the H—N—H bond angle Pyramidal geometry at sp3-hybridised N in methylamine, CH3NH2 Planar geometry at sp2-hybridised N in formamide, HC(=O)NH2 147 pm sp3 sp2 112° ~125° 106° 180° METHYLAMINE (1O AMINE) FORMAMIDE (1o AMIDE) Slide 11 MPharm PHA114 Amines 1 WEEK 19 Chirality Is Possible (But Not Observed) An amine with three different substituents on nitrogen is chiral (in principle, but not in practice) – the lone pair of electrons is the fourth substituent – most amines having three different substituents on N are not resolved because the molecules interconvert by pyramidal inversion Slide 12 MPharm PHA114 Amines 1 WEEK 19 Chirality of Amines – Exceptions Pyramidal inversion is not possible with quaternary ammonium ions, and their salts can be resolved Me Ph Cl Ph Me Cl N N R-isomer S-isomer Slide 13 MPharm PHA114 Amines 1 WEEK 19 Amines Form Hydrogen Bonds Amines can form hydrogen bonds N-H bond is less polar than O-H bond – weaker hydrogen bonding A … H_D A … H_D Hydrogen bonds strength: O-H----O stronger than N-H----N C H 3N H 2 C H 3O H Difference in electronegativity: M W 3 1.1 3 2.0 between O and H : 3.5 - 2.1 = 1.4 b p - 6.3 6 5.0 between N and H : 3.0 - 2.1 = 0.9 Slide 14 MPharm PHA114 Amines 1 WEEK 19 Basicity of Amines The lone pair of electrons on nitrogen makes amines basic and nucleophilic They react with acids to form acid–base salts and they react with electrophiles Slide 15 MPharm PHA114 Amines 1 WEEK 19 Basicity of Amines amine salts are ionic and therefore more soluble in water than the parent amines For this reason, amine drugs are often given in the form of salts as they will readily dissolve in body fluids HO H H CH3 N H N CH3 O H CH3 H CH3 Cl Cl pseudoephedrine hydrochloride diphenhydramine hydrochloride Slide 16 MPharm PHA114 Amines 1 WEEK 19 Cocaine Cocaine is sold illegally as the hydrochloride salt or as the free amine [‘crack’ cocaine] H CH3 CH3 N O N O OCH3 base OCH3 O O Cl O O cocaine hydrochloride cocaine (free base) 'crack cocaine' coca plant Erythroxylon coca Slide 17 MPharm PHA114 Amines 1 WEEK 19 Amine Salts Ionic solids with high melting points Soluble in water Generally odourless, stable Reversible conversion to ‘free’ amine (may have odour, can be unstable to oxidation) cf. purification of carboxylic acids !! Slide 18 MPharm PHA114 Amines 1 WEEK 19 Purifying an Amine Slide 19 MPharm PHA114 Amines 1  3 WEEK O HO 19 Me O O Pain Treatment OH O H N Me HO Aspirin and morphine both treat pain aspirin 6 morphine Aspirin (NSAID) prevents the synthesis of prostaglandins and inhibits release of pyrogens (treats cause of pain) Morphine blocks the nerve impulse that signals pain – interaction with opiod receptors throughout the CNS and also in GI tract – block transmission of nerve impulses (pain) to the brain multiple-site binding … sleepiness and well- being – also interact with sites in brain associated with pleasurable sensation sites activated by endorphins – endorphin … endogenous morphine pleasurable sensation and euphoria potential for abuse narcotic Slide 20 MPharm PHA114 Amines 1