Medical Chemistry Lecture 2024 PDF

Week 9 Lectures 1-2 Medical Chemistry Lecture 2024 Organic Halogen Compounds, Alcohols, Phenols and Ethers, Organic Sulphur Compounds Viktor Dombrádi (GenMed) Peter Bay (Dent)...

Week 9 Lectures 1-2 Medical Chemistry Lecture 2024 Organic Halogen Compounds, Alcohols, Phenols and Ethers, Organic Sulphur Compounds Viktor Dombrádi (GenMed) Peter Bay (Dent) Department of Medical Chemistry UD Faculty of Medicine Organic Halogen Compounds F, Cl, Br, I Alkyl halide: a compound containing a halogen atom covalently bonded to an sp3 hybridized carbon atom R X A haloalkane (an alkyl halide) If the halogen is bonded to an sp2 hybridized carbon, the compound is called a vinylic halide If the halogen is bonded to a benzene ring, it is called an aryl halide, given the symbol Ar-X R X C C X R R A haloalkene A haloarene (a vinylic halide) (an aryl halide)  Synthesis Substitution of alkanes for example chlorination of methane in a chain reaction : Products:  Synthesis Addition to alkenes C C + Br2 C C of Br2 for instance: Br Br or of HBr for instance: C C + HBr C C H Br Substitution of aromatic compounds with Br2 for instance: CH3 CH3 CH3 catalyst Br + Br Br + Br  Reactions Nucleophilic Substitution nucleophilic - substitution X- Nu + C X C Nu + Nucleophilic substitution: any reaction in which one nucleophile is substituted for another Nucleophile: a molecule or ion that donates a pair of electrons to another molecule or ion to form a new covalent bond: a Lewis base The most important reactions of alkyl halides Reaction: + + - Nu CH 3 Br CH 3 Nu Br - HO CH 3 OH an alcohol - RO CH 3 OR an ether - HS CH 3 SH a thiol (a mercaptan) - RS CH 3 SR a sulfide (a thioether) - I CH 3 I an alkyl iodide + NH 3 CH 3 NH 3 an alkylammonium ion + HOH CH 3 O-H an alcohol (after proton transfer) H  Mechanisms Chemists propose two limiting mechanisms for nucleophilic aliphatic substitution a fundamental difference between them is the timing of bond-breaking and bond-forming steps they are designated SN1 and SN2  Mechanism - SN2 Bond breaking and bond forming occur simultaneously S = substitution N = nucleophilic 2 = bimolecular Bimolecular reaction: a reaction in which two reactants are involved in the transition state of the rate-limiting step  Mechanism - SN2 Simultaneous backside attack of the nucleophile and departure of the leaving group  Dependence on the structure of alkyl group R SN2 Nu C X fast H H R primary halide (rear side not crowded) SN2 Nu C X slow R SN1, faster R tertiary halide (rear side crowded)  Mechanism - SN1 Bond breaking is complete before bond forming begins S = substitution N = nucleophilic 1 = unimolecular Unimolecular reaction: a reaction in which only one species is involved in the transition state of the rate-limiting step  Mechanism - SN1 Step 1: ionization of the C-X bond to form a carbocation intermediate (slow rate limiting step) Step 2: reaction of the carbocation with the nulcleophile (fast reaction)  b-Elimination b-Elimination: removal of atoms or groups of atoms from adjacent carbons to form a carbon- carbon double bond b  C C + CH 3 CH 2 O - Na + CH 3 CH 2 OH H X Base An alkyl halide C C + CH 3 CH 2 OH + Na + X - An alkene IMPORTANT ORGANIC HALOGEN COMPOUNDS Natural hormones: I I NH3+ HO O CH2 - C COO I I H Thyroxine, T4 I I NH3+ HO O CH2 - C COO I H Triiodothyronine, T3 Inhalational Anaestetics  CHLOROFORM 1847 Sir James Simpson Reacts with the oxygen of the air in the presence of light : hν 2CHCl3 + O2 = 2COCl2 + 2HCl Phosgene, highly toxic! Chloroform causes delayed liver injury.  Modern Inhalational Anaestetics ENFLURane ISOFLURANE DESFLURANE SEVOFLURANE PHARMACOLOGY The introduction of halogen atoms into the drug molecules makes the more watersoulbe and more stable, like cholrohexidine an antimicrobial agent. SOME PROBLEMATIC HALOGEN DERIVATIVES  Dichlorodiphenyltrichloroethane (DDT) an insecticide; was BANNED as it accumulates in the adipose tissue.  Chlorinatedphenoxyacetic acid (2,4-D and 2,4,5-T) herbicides; were BANNED due to their carcinogenic dioxin contamination.  Chlorofluorocarbon (CFC) insulating and cooling gases; were BANNED since they damage the stratospheric ozone layer. Most of the halogen containing organic compounds are foreign to the living organisms. They are not metabolized, rather they accumulate in the environment and in our own body. Alcohols and Phenols Introduction General formula: R-OH That is: aliphatic and aromatic compounds containing a hydroxyl (OH) group. R = alkyl, substance is an alcohol. R = aryl, substance is a phenol. Alcohols - Classification There are three types of alcohols. Primary Secondary Tertiary This refers to the substitution pattern on the carbon carrying the hydroxyl (OH) group. Alcohols - Classification CH3 CH2 OH CH3 CH CH3 CH3 OH CH3 C CH3 1° 2° OH 3° If only one carbon bound to the C containing the OH Primary. Primary is indicated by 1°. Two carbons bound to the C with the OH  Secondary. Secondary is shown by 2°. Three Tertiary. Tertiary is displayed as 3°. Alcohols - Forces between molecules Alcohols (like water) contain an OH group that can make a hydrogen bond to other polar groups. Hydrogen bonding requires: a lone pair a polarised bond  - R O  + H Alcohols - Polarised OH group Region of negative character. R O H Region of positive character. Polarisedbond due to electronegativity differences. Alcohols – Hydrogen bridges O R etc. H H R O O H R H O R etc. A network builds up which needs energy to break apart.  Alcohols - Boilingpoints 150 117 100 97 78 65 50 36 BP 0 0 30 32 44 46 58 60 72 74 Mol. Wt. -42 -50 Boiling Pt. -88 (Alkane) -100 Boiling Pt. (ROH) Alcohols – Water solubility 10 Water solubility (g/100ml) 1-butanol 8 6 Water Solubility 4 (g/100 ml) 1-pentanol 2 1-hexanol 1-heptanol 0 1 2 3 4 5 6 7 8 9 10 1 3 4 6 8 10 Number Number of carbon of carbon atoms inatoms molecule Alcohols - Synthesis Hydrolysis of alkyl halides: - + Br - H O C Br H O C Hydration of alkenes: H H H2SO4 C C + H2O CH3 CH2 OH H H  Alcohols can be made via reduction Carboxylic acids and aldehydes give primary alcohols. O CH3 C OH LiAlH 4 CH3 CH2 OH O CH3 C H Ketones produce secondary alcohols: O OH LiAlH 4 CH3 C CH3 CH CH3 CH3 Ethanol is made by fermentation C6O6H12 2 C2H5OH + 2 CO2  Alcohols –Chemical properties In dilute aqueous solution, alcohols are weakly acidic + - CH 3 O-H + O H CH 3 O + H O H H H [CH 3 O - ] [H 3 O + ] Ka = = 15.5 CH3CH2 - OH [CH 3 OH] CH3CH2 - O ethanol pKa ~ 16 ethoxy anion  Acid Strength Compound Formula pKa hydrogen chloride HCl -7 Stronger acid acetic acid CH 3 CO2 H 4.8 methanol CH 3 OH 15.5 water H2 O 15.7 ethanol CH 3 CH 2 OH 15.9 2-propanol (CH 3 ) 2 CHOH 17 Weaker 2-methyl-2-propanol (CH 3 ) 3 COH 18 acid Electron donor groups(+I effect) decrease acidity. Alcohols – Chemical Reactions Dehydration H2SO4 C C C C + H2O 180° C H OH Esterification (with inorganic acids) Ether formation CH3-OH + Cl-CH3 CH3-O-CH3 + HCl  Oxidation of alcohols CH 3 OH OX. H C H OX. H C OH O O methanol  methanal  methanoic acid  CH3 CH2 OH OX. CH 3 C H OX. CH3 C OH O O ethanol  H C H ethanal  H C OH ethanoic acid O O primary alcolhol aldehyde carboxylic acid H OX. CH3 C CH3 CH3 C CH3 OH O 2-propanol propanone secondary alcohol ketone  Alcohols - Toxicity Methanol is very toxic. 15 mls blinds.  30 mls kills. Ethanol is less toxic.  However 600 mls will kill. Ironicaly the treatment for methanol poisoning is to drink lots of ethanol! Phenols Molecules where the hydroxyl group is bound to an aromatic ring are phenols. Phenols display similar hydrogen bonding properties as alcohols. The OH bond is polarised, solubility and boiling point are affected. The simplest phenol is phenol itself.  Phenol Derivatives OH OH OH Cl CH3 OH o-chlorophenol m-cresol hydroquinone Most often they are designated by trivial names  Phenols - Properties Phenols differ from alcohols as they are slightly acidic. A solution of phenol in water is known as Carbolic Acid. This was used in the 1860s by Lister to kill bacteria. Lister’s use of this antiseptic revolutionized surgery. Phenols -Acidity Phenols are slightly acidic. pKa for phenol is about 10. OH O H + Stability of the phenolate anion O O O O O  - - - - The phenolate anion is stabilized by the delocalization of the negative charge. Comparison of Alcohols with Phenols Phenols are stronger acids than the alcohols.  Effect of other substituents on the acidity of phenols Electron withdrawing groups (–I effect) increase acidity. Phenols - Reactions - OH O Na+ NaOH H2O +  Oxidation of phenols OH O OX. red. OH O 1,4-dihydroxybenzene 1,4-benzoquinone (hydroquinone) phenol quinone The redox-reaction proceeds via semiquinone radical intermediate. Ethers Introduction General formula : R-O-R where R can be the same group or different, aromatic or aliphatic. The functional group of an ether is an oxygen atom bonded to two carbon atoms. They are slightly polar due to the lone pairs on the oxygen. They are chemically very inert. H H H C O C H H H Derivation of ethers: H H R H R R O O O water alcohol ether Preparation of ethers: 1. From alcohols by elimination of water R-OH + R’-OH R-O-R’ -H2O ether 2. From alcoholates and alkyl halides R-ONa + R’-Cl R-O-R’ -NaCl ether  CLASSIFICATION OF ETHERS Alkyl ethers: Aromatic ethers: Cyclic ethers: Epoxides: rings break open easily  Biological significance of epoxides Formation of epoxides is important in amino acid biosynthesis: But the same enzymes can catalyze the bioactivation of benzene: and convert carcinogenic compounds to a reactive (mutagenic) form: not soluble partially soluble  Physical Properties of Ethers Because of the lack of internal hydrogen bonds they have low boiling points: e.g. diethyl ether BP = 35°C However the lone pairs on the oxygen allow hydrogen bonding with water and hence they are more soluble than alkanes and approach alcohols of equivalent weights. These properties make ethers important as solvents and anaesthetics. CH3 CH2 O CH2 CH3 W. T. G. Morton, 1846  Reactions of Ethers Like the alkanes ethers exhibit low reactivity. The oxidation of ethers by the oxygen in the presence of light produces harmful peroxides O2 h While the ether is flammable the more reactive peroxide is a friction-sensitive exposive! Keep ether in dark bottle and exclude oxygen by topping up, and add antioxidant to it! Organic Sulphur Compounds Important sulphur containing organic compounds  Thiols Thiols, also called mercaptans, are sulfur analogs of alcohols. They are named by the same system used for alcohols, with the suffix -thiol used in place of -ol. The –SH group itself is referred to as a mercapto group. Like alcohols, thiols are weakly acidic; e.g. the pK of CH3SH, is 10.3 but thiols are more acidic than alcohols. Unlike alcohols, however, thiols don’t form hydrogen bonds because the sulfur atom is not sufficiently electronegative.  Sulfides Sulfides are the sulfur analogs of ethers just as thiols are the sulfur analogs of alcohols. Sulfides are named by following the same rules used for ethers, with sulfide used in place of ether for simple compounds, and alkylthio used in place of alkoxy for the more complex substances. Sulfides can be synthetised from thiols with alkyl halides. Oxidadtion of Thiols and Sulfides Protein Forming S-containing Amino Acids L-cysteine, Cys, C Significance: Structure of proteins Enzyme activity Protective functions thiol L-methionine, Met, M tioether Significance: Methyl group transfer (SAM)  Coenzyme A (CoA) Reactive thiol group It is an active-acetate carrier nucleotide coenzyme (AcCoA), that plays a central role in metabolism.