PHA114 Amines 2 - PDF

WEEK 19 MPharm Programme PHA114 Amines 2 Dr. Matt Smith Slide 1 MPharm PHA114 Amines 2 WEEK 19 Basicity All amines are weak bases, and aqueous solut...

WEEK 19 MPharm Programme PHA114 Amines 2 Dr. Matt Smith Slide 1 MPharm PHA114 Amines 2 WEEK 19 Basicity All amines are weak bases, and aqueous solutions of amines are basic – amines are stronger bases than alcohols, ethers, or water – amines establish an equilibrium with water in which the amine becomes protonated and hydroxide is produced H H + - :O-H CH 3 - N: + H- O-H CH3 - N- H H H Methylamine M ethylammonium hydroxide [CH 3 NH 3 + ][OH - ] Kb = K eq [H 2 O] = = 4.37 x 10-4 [CH 3 NH 2 ] Slide 2 MPharm PHA114 Amines 2 WEEK 19 Basicity It is more common to discuss the basicity of an amine (RNH2) by reference to the acidity of the corresponding ammonium ion (conjugate acid), RNH 3+ CH3 NH 3 + + H2 O CH3 NH 2 + H3 O+ [ CH3 NH 2 ] [ H3 O+ ] Ka = = 2.29 x 10-11 pK a = 10.64 + [ CH3 NH 3 ] Remember: high pKa → weaker acid and stronger conjugate base (more basic amine) for any acid-conjugate base pair: pK a + pK b = 14.00 Slide 3 MPharm PHA114 Amines 2 WEEK 19 Inductive Effect Alkyl groups – electron-donating and stabilise the cation (c.f. SN1 reactions). – electron withdrawing groups will destabilise the cation. Solvation – hydrogen bonding with water donates electrons and stabilises the cation. Methyl group increases electron density on N – 2 methyls are better than one. However, 3 methyl groups decreases basicity! – steric inhibition of solvation of HOH with the NH+ of the R3NH+ cation. Slide 4 MPharm PHA114 Amines 2 WEEK 19 General Patterns of Basicity The greater the availability of the lone pair electrons on nitrogen, the greater the base strength Most simple alkylammmonium ions have pKa's of 9 to 11 25% ‘s’ 33% ‘s’ 50% ‘s’ Arylamines and heterocyclic aromatic amines are considerably less basic than alkylamines – lone pair in sp2 orbital – conjugate acid pKa typically 5, or less Slide 5 of 24 MPharm PHA111 Amines 2 WEEK 19 Basicity - Aromatic Amines Aromatic amines are considerably weaker bases than aliphatic amines. The N lone-pair electrons in arylamines are delocalised by interaction with the aromatic ring  electron system. Lone pair of electrons in aromatic amine less available act as nucleophile or basic Less able to accept H+ than alkylamines No resonance stabilisation ED of electrons EW of electrons Slide 6 MPharm PHA114 Amines 2 WEEK 19 Resonance Effects Any delocalisation of the electron pair weakens the base (less available to accept a proton) Slide 7 MPharm PHA114 Amines 2 WEEK 19 Hybridisation Effects Electrons are held more tightly in orbitals with more s character, so those compounds are weaker bases Heterocyclic aromatic amines are weaker bases than heterocyclic aliphatic amines Pyridine is a weaker base than heterocyclic aliphatic amines In pyridine, the unshared pair of electrons on N is not part of the aromatic sextet The free electron pair on N lies in an sp2 hybrid orbital (33% s character) and is held more tightly to the nucleus than the free electron pair on N in an sp3 hybrid orbital (25% s character) Slide 8 MPharm PHA114 Amines 2 WEEK 19 Basicity - Aromatic Amines Aromaticity is maintained when imidazole is protonated HN 6.0 (protonated imine) N pKa H2N CO2H 1.8 pKa 9.2 (protonated amine) pKa amino acid : histidine Slide 9 MPharm PHA114 Amines 2 WEEK 19 Basicity - Guanidine Guanidine is the strongest base among neutral organic compounds Enhanced basicity is due to the delocalisation of the positive charge over the three nitrogen atoms (three equivalent resonance structures) HN NH2 12.5 (protonated imine) pKa NH amino acid - arginine H2N CO2H 9.0 (protonated amine) 2.2 pKa pKa Slide 10 MPharm PHA114 Amines 2 WEEK 19 Acid–Base Properties of Amino Acids In neutral solution, the -CO2H is ionised and the -NH2 is protonated The resulting structures have “+” and “-” charges (a dipolar ion, or zwitterion) They are like ionic salts in solution Slide 11 MPharm PHA114 Amines 2 WEEK 19 Acid–Base Properties of Amino Acids An amino acid can never exist as an uncharged compound Amino acids have pKa values for the carboxyl group, amino group, and in some cases their R-group – charged R groups are extremely important in the structure and function of proteins Slide 12 MPharm PHA114 Amines 2 WEEK 19 Titration Curves of Amino Acids pH = pKa + log [A-]/[HA] pH = pKa + log [B]/[BH+] Slide 13 MPharm PHA114 Amines 2 WEEK 19 Amides Remember - amides (RCONH2) are not proton acceptors – the C=O group is strongly electron-withdrawing, making the N a very weak base Addition of a proton can occur on oxygen of C=O – this destroys the double bond character of C=O as a requirement of stabilisation by N – makes amides more reactive to nucleophilic addition-elimination O O N N -H +H H H O O N N Slide 14 MPharm PHA114 Amines 2 WEEK 19 Synthesis of Amines : Reduction of Nitriles and Amides Slide 15 MPharm PHA114 Amines 2 WEEK 19 Reduction Of Aryl Nitro Compounds Arylamines are prepared from nitration of an aromatic compound and reduction of the nitro group Reduction by catalytic hydrogenation over platinum is suitable if no other groups can be reduced Iron, zinc, tin, and tin(II) chloride are effective in acidic solution Chemistry of aryl amines – Sem 2 Slide 16 MPharm PHA114 Amines 2 WEEK 19 Synthesis of Amines : SN2 Reactions of Alkyl Halides Ammonia and other amines are good nucleophiles Primary, secondary, and tertiary amines all have similar reactivity, the initially formed monoalkylated substance undergoes further reaction to yield a mixture of products Unfortunately, such alkylations give mixtures of products through a series of proton transfer and nucleophilic substitution reactions Slide 17 MPharm PHA114 Amines 2 WEEK 19 Reactions of Amines : Reactions with Carboxylic Acid Derivatives Slide 18 MPharm PHA114 Amines 2 WEEK 19 Nucleophilic Addition to Carbonyls RNH2 adds to C=O to form imines – C=O replaced by C=N-R – nucleophilic-addition-elimination mechanism – elimination of water aniline benzaldehyde an imine Slide 19 MPharm PHA114 Amines 2 WEEK 19 Reductive Amination of Aldehydes and Ketones Treatment of an aldehyde or ketone with ammonia or an amine in the presence of a reducing agent (reduces C=N but not C=O) Slide 20 MPharm PHA114 Amines 2 WEEK 19 Reactions of Amines : Formation of Sulfonamides Primary or secondary amines react with sulfonyl chloride to produce sulfonamides (c.f. reactions of acid chlorides!) Sulfa drugs : sulfonamides antibacterial agents O O O O N O S S CH3 NH 2 N H H2N H2N sulanilamide sulfamethoxazole Slide 21 MPharm PHA114 Amines 2 WEEK 19 analogous reaction to acid chlorides and amines acidic NH2 basic NH2 Slide 22 MPharm PHA114 Amines 2 WEEK 19 Folic acid vital for humans and bacteria humans obtain from diet bacteria synthesise it => selectivity of action Better agents now available many sulfonamides display diuretic activity Slide 23 MPharm PHA114 Amines 2 WEEK 19 Further Reading/References Bruice, Organic Chemistry – Amines Organic Chemistry – Relevant chapters in books by McMurray, Solomons, Wade, Fox etc. Slide 24 MPharm PHA114 Amines 2