MPharm Programme PHA111 Functional Group Chemistry 3 PDF

WEEK 11 MPharm Programme PHA111 Functional Group Chemistry 3 Dr. Stephanie Myers Senior Lecturer in Medicinal Chemistry...

WEEK 11 MPharm Programme PHA111 Functional Group Chemistry 3 Dr. Stephanie Myers Senior Lecturer in Medicinal Chemistry Dale 1.21 [email protected] Telephone: 0191 5152760 Slide 1 of 25 MPharm PHA111 Functional Group Chemistry WEEK 11 Learning Objectives 1. Describe and explain the differences in physical properties of aliphatic alcohols, phenols and haloalkanes with respect to their chemical structure and intermolecular interactions 2. List the reactions which can be used to prepare alcohols, and the reactions which alcohols can undergo, including the relevant reagents and conditions 3. Understand the reactivity of alcohols and alkyl halides with respect to a nucleophilic substitution type reaction 2 Slide 2 of 25 MPharm PHA111 Functional Group Chemistry WEEK 11 Alcohols: General Properties Unsaturated or saturated compounds Contain C-O-H single bonds Hydroxyl/alcohol is functional group Oxygen is sp3 hybridised Similar structure to water –lone pairs to donate Act as nucleophiles Reactivity controlled by electron rich oxygen atom pKa range = 15.5-18.0 (phenols ~10) Sub-classified as follows: 3 Slide 3 of 25 MPharm PHA111 Functional Group Chemistry WEEK 11 Alcohols: pKa pKa range = 15.5-18.0 Acidity decreases as alkyl substitution increases –positive inductive effect Alkyl groups are electron donating Acidity increases with number of halogen substituents –negative inductive effect Halogens are electron withdrawing pKa is dependent on the ability of neighbouring groups/substituents to stabilise (or destabilise!) the resulting negative charge Phenol is 100 million times more acidic than cyclohexanol Negative charge stabilised by resonance 4 Slide 4 of 25 MPharm PHA111 Functional Group Chemistry WEEK 11 Alcohols: pKa Alcohol Structure Ka pKa Methanol CH3OH 3.2 x 10-16 15.5 Ethanol CH3CH2OH 1.3 x 10-16 15.9 2-chloroethanol ClCH2CH2OH 5.0 x 10-15 14.3 2,2,2- Cl3CH2OH 6.3 x 10-13 12.2 trichloroethanol Isopropyl alcohol (CH3)2CHOH 3.2 x 10-17 16.5 t-Butyl alcohol (CH3)3COH 1.0 x 10-18 18.0 Cyclohexanol C6H11OH 1.0 x 10-18 18.0 Phenol C6H5OH 1.0 x 10-10 10.0 Comparison with other acids Water H2O 1.8 x 10-16 15.7 Acetic acid CH3COOH 1.6 x 10-5 4.8 Hydrochloric acid HCl 1.6 x 102 -2.2 5 Slide 5 of 25 MPharm PHA111 Functional Group Chemistry WEEK 11 Alcohols: Physical Properties Similar increases in melting point/boiling point across the homologous series Unusually high boiling points due to H-bonding between molecules Small alcohols are miscible with water, but solubility decreases as the size of the alkyl group increases Like dissolves like 6 Slide 6 of 25 MPharm PHA111 Functional Group Chemistry WEEK 11 Alcohols: Preparation Preparation Methanol Toxic dose 100 mL Ethanol Industrially produced by fermentation of starch and grains Toxic dose 200 mL More complex alcohols are prepared using 3 main methods Hydration of alkenes –see FGC L2 Hydrolysis of alkyl halides Nucleophilic substitution reactions Reduction of carbonyl compounds E.g. aldehydes, ketones, carboxylic acids, esters 7 Slide 7 of 25 MPharm PHA111 Functional Group Chemistry WEEK 11 Reduction of Carbonyl Compounds Alcohols can be prepared from the reduction of a variety of carbonyl-containing compounds Aldehydes, ketones, esters, carboxylic acids O H R O Reduction CARBOXYLIC ACID O OH H O OH Reduction Reduction R H R H R R1 R R1 H H ALDEHYDE H KETONE H PRIMARY SECONDARY ALCOHOL H ALCOHOL O Reduction R1 R O CARBOXYLIC ESTER 8 Slide 8 of 25 MPharm PHA111 Functional Group Chemistry WEEK 11 Reduction of Carbonyl Compounds Aldehydes and Ketones can be reduced by both: Sodium borohydride (NaBH4) Lithium aluminium hydride (LiAlH4) These reagents both act as sources of hydride (H-) Like addition of H-H across C=O Acids and Esters can only be reduced by LiAlH4 9 Slide 9 of 25 MPharm PHA111 Functional Group Chemistry WEEK 11 Alcohols: Useful Reagents 10 Slide 10 of 25 MPharm PHA111 Functional Group Chemistry WEEK 11 Alcohols: Reactivity Completely burn in O2 Alkoxideformation React alcohol with sodium metal (redox reaction) E.g. ethanol → ethoxide Ester formation Important in biological processes Oxidation Opposite of reduction E.g. C-O-H→ C=O Reaction with HX Conversion to haloalkanes 11 Slide 11 of 25 MPharm PHA111 Functional Group Chemistry WEEK 11 Ester Formation Fischer Esterification A classical transformation Condensation process H2O produced Acid catalysed H2SO4is a source of H+ and a dehydrating agent Reversible reaction Series of equilibria Aqueous acid hydrolyses esters to carboxylic acids 12 Slide 12 of 25 MPharm PHA111 Functional Group Chemistry WEEK 11 Oxidation High oxidation state metal salts are useful oxidising agents, which are soluble in water 13 Slide 13 of 25 MPharm PHA111 Functional Group Chemistry WEEK 11 Biological Oxidation of Alcohols Two step process within the body Carried out by enzymes NAD+ as a coenzyme Alcohol dehydrogenase Converts to aldehyde OH → CHO Aldehyde dehydrogenase Converts to acid CHO → COOH 2nd step can be inhibited by disulfiram (Antabuse) disulfiram 14 Slide 14 of 25 MPharm PHA111 Functional Group Chemistry WEEK 11 Addition of H-X Addition of HCl, HBr or HI Displacement of hydroxyl group Replace with halogen A nucleophilic substitution reaction Formation of an haloalkane Alkyl halide We look at the mechanistic implications later on…. 15 Slide 15 of 25 MPharm PHA111 Functional Group Chemistry WEEK 11 Phenols Very different properties to aliphatic alcohols Phenols are planar C-O bond distance is 136 pm, which is slightly shorter than that of CH3OH (142 pm) Unusual H-bonding The hydroxyl group of phenol allows H-bonding to other phenol molecules and to water Slide 16 of 25 MPharm PHA111 Functional Group Chemistry WEEK 11 Phenols Compared to compounds of similar size and molecular weight H-bonding in phenol: Raises its melting point Raises its boiling point Increases its solubility in water More acidic than aliphatic alcohols Lower pKa~10 Phenoxide ion stabilised by resonance 17 Slide 17 of 25 MPharm PHA111 Functional Group Chemistry WEEK 11 Phenols: Biologically Important Epinephrine/Adrenaline Is the principal hormone governing the “flight or fight” response. This hormone also triggers a variety of physiological events, including increased heart rate. It is biosynthesized from the amino acid tyrosine by way of DOPA. 18 Slide 18 of 25 MPharm PHA111 Functional Group Chemistry WEEK 11 Haloalkanes: General Unsaturated or saturated compounds Contain C-X bond Also known as alkyl halides Halogens are more electronegative than carbon C-X bond is polar, so C has a partial positive charge δ+ Act as electrophiles Reactivity controlled by electron poor carbon atom Can be attacked by a nucleophile Halogen is the leaving group which takes an electron pair 19 Slide 19 of 25 MPharm PHA111 Functional Group Chemistry WEEK 11 Haloalkanes: Anaesthetics Diethyl Ether (ether) first used in late 1800s (dentistry) Accumulates in lipid membrane of nerve cells and interferes with transmission of nerve impulses Very flammable, low flash point Replaced with halothanes H H H H H H C C Cl H C Cl H C C Cl H H H H Br HALOTHANE H H H H Local Anaesthetics General Anaesthetics H C C O C C H H H H H H F Cl F F F Diethyl ether 'ETHER' H C O C C Cl H C O C C Cl H F H F F H PENTHRANE ENTHRANE General Anaesthetics 20 Slide 20 of 25 MPharm PHA111 Functional Group Chemistry WEEK 11 Haloalkanes: Physical Properties For an alkane and a haloalkane of comparable size and shape, the haloalkane has the higher boiling point CH3 CH3 CH3 Br The difference is due almost entirely to the greater polarisability of C-X bond bp -89°C bp 4°C The densities of liquid haloalkanes are greater than those of hydrocarbons of comparable D ens ity (g/mL) at 25°C molecular weight Haloalkane X= Cl Br I All liquid bromoalkanes and iodoalkanes are CH2 X2 1.327 2.497 3.325 more dense than water CHX3 1.483 2.890 4.008 CX4 Di- and polyhalogenated alkanes are more 1.594 3.273 4.23 dense than water 21 Slide 21 of 25 MPharm PHA111 Functional Group Chemistry WEEK 11 Haloalkanes: Reactivity Preparation Free radical substitution of alkanes (see FGC L1) Electrophilic addition (H-X) to alkenes (see FHC L2) Halogenation (Br2/Cl2) of alkenes or alkynes Halogenation (H-X) of alcohols Reactivity Nucleophilic substitution Alkyl halides are polarised at the C-X bond, making the carbon atom electrophilic Nucleophiles will replace the halide in C-X bonds of many alkyl halides Nucleophilic substitution reactions can follow two distinct mechanistic pathways…. 22 Slide 22 of 25 MPharm PHA111 Functional Group Chemistry WEEK 11 Haloalkanes: Reactivity How do haloalkanes react? Alternatively 23 Slide 23 of 25 MPharm PHA111 Functional Group Chemistry WEEK 11 SN1 and SN2 Reactions Because a nucleophile substitutes for the halogen, these reactions are known as nucleophilic substitution pathways Can follow first or second order reaction kinetics Ingold nomenclature to describe characteristic step: S = Substitution N = Nucleophilic 1 = Only substrate is involved in the characteristic step (i.e. reaction is unimolecular) 2 = Both nucleophile and substrate are involved in the characteristic step (i.e. reaction is bimolecular) 24 Slide 24 of 25 MPharm PHA111 Functional Group Chemistry  Further Reading/References 25 Slide 25 of 25 MPharm PHA111 Functional Group Chemistry