Week 11 Functional Group Chemistry 4 (MPharm Programme) PDF

WEEK 11 MPharm Programme PHA111 Functional Group Chemistry 4 Dr. Matt Smith Lecturer in Biochemistry Dale 1.21 [email protected] Slide 1 of 29 MPharm PHA111 Functional Group Chemistry WEEK 11 Learning Objectives 1. Deduce with rational explanations whether a reaction will proceed...

WEEK 11 MPharm Programme PHA111 Functional Group Chemistry 4 Dr. Matt Smith Lecturer in Biochemistry Dale 1.21 [email protected] Slide 1 of 29 MPharm PHA111 Functional Group Chemistry WEEK 11 Learning Objectives 1. Deduce with rational explanations whether a reaction will proceed via an SN1 or SN2 reaction mechanism with respect to the reagents used and reaction conditions 2. Describe and explain the physical and chemical properties of amines including their ability to react as nucleophiles 3. Give example reactions (including appropriate reagents and conditions) in which amines can be utilised in drug syntheses 4. Appreciate the synthetic challenges which can arise when trying to alkylate amines via nucleophilic substitution reactions and suggest how this can be circumvented in practice 5. Describe the physical properties of amino acids which contain two ionisable functional groups with reference to ionisation Slide 2 of 29 MPharm PHA111 Functional Group Chemistry 2 WEEK 11 The SN1 and SN2 Mechanisms The reaction mechanism which will predominate depends on the following factors: • Structure of the alkyl halide • Reactivity of the nucleophile • Concentration of the nucleophile • Solvent used for the reaction The study of rates of reactions is called kinetics The order of a reaction is the sum of the exponents of the concentrations of reagents which are in the rate law • Depends which reagents are involved in the rate determining step Slide 3 of 29 MPharm PHA111 Functional Group Chemistry 3 WEEK 11 Three Experimental Evidences Support an SN2 Mechanism 1. The rate of reaction us dependent on the concentration of both the haloalkane and the nucleophile 2. The rate of reaction with a given nucleophile decreases with increasing size of the haloalkane 3. If a chiral alkyl halide is used, the chirality of the substituted product is inverted relative to the starting material Slide 4 of 29 MPharm PHA111 Functional Group Chemistry 4 WEEK 11 Size of the Alkyl Halide The rate of reaction with a given nucleophile decreases with increasing size of the haloalkane Slide 5 of 29 MPharm PHA111 Functional Group Chemistry 5 WEEK 11 SN2 Reaction Mechanism • One step reaction –concerted • Transition state is highest in energy species • Activation energy is lower for SN2 reaction of methyl bromide than that needed to react a sterically hindered alkyl bromide Slide 6 of 29 MPharm PHA111 Functional Group Chemistry 6 WEEK 11 SN2 Transition State • The TS of an SN2 reaction has a planar arrangement of the carbon atom and the remaining three groups Slide 7 of 29 MPharm PHA111 Functional Group Chemistry 7 WEEK 11 Inversion of Stereochemistry • Chirality of the substituted product is inverted with respect to the chirality of the reacting alkyl halide • Inversion of stereochemical configuration in the SN2 reaction is to due to back side attack • • Walden Inversion Umbrella analogy • Incoming nucleophile approaches from the opposite face to the leaving group Slide 8 of 29 MPharm PHA111 Functional Group Chemistry 8 WEEK 11 Nature of the Nucleophile • SN2 reactions are affected by the nature of the attacking nucleophile • Nucleophilicity is a measure of how readily a compound is able to react with (attack) an electron-deficient atom • Polarisability is a measure of how well a nucleophile can encroach on the orbital used for bonding in the electrophile • Atoms with larger electron shells (those found lower in the group in the periodic table) are generally better nucleophiles (better orbital overlap) • HS- is more nucleophilic than HO• Halide reactivity order is I- > Br- > Cl- Slide 9 of 29 MPharm PHA111 Functional Group Chemistry 9 WEEK 11 Nature of the Nucleophile • Basicity is a measure of how well a compound is willing to donate a lone pair of electrons to a proton • Bases are therefore nucleophiles • Measured using the acid dissociation constant (Ka, pKaof the conjugate acid) • More basic nucleophiles are more reactive • Negatively charged species are stronger nucleophiles Slide 10 of 29 MPharm PHA111 Functional Group Chemistry WEEK 11 Solvent Effects • Solvents that can form Hbonds (OH or NH containing) slow SN2 reactions down by associating with reactants • Energy is required to break interactions between reactant and solvent • Polar aprotic solvents (no NH,OH, SH) permit faster reactions Slide 11 of 29 MPharm PHA111 Functional Group Chemistry 11 WEEK 11 Nature of the Leaving Group • A good leaving group reduces the barrier for a reaction to occur • Stable anions that are weak bases are usually excellent leaving groups as they can stabilise the resulting negative charge • The weaker the base the better the leaving group • If a leaving group is very basic or very small it can prevent the reaction taking place Slide 12 of 29 MPharm PHA111 Functional Group Chemistry WEEK 11 Three Experimental Evidences Support an SN1 Mechanism 1. The rate of reaction us dependent on the concentration of only the haloalkane 2. The rate of reaction is favoured by the bulkiness of the alkyl substituent 3. If a chiral alkyl halide is used, the substitution reaction results in a racemic mixture of products Slide 13 of 29 MPharm PHA111 Functional Group Chemistry 13 WEEK 11 SN1 Mechanism The rate of the reaction depends only on the concentration of the haloalkane • Increasing [Nuc-] has no effect on rate • RDS is loss of the leaving group/formation of the carbocation Slide 14 of 29 MPharm PHA111 Functional Group Chemistry 14 WEEK 11 Nature of the Alkyl Substituent Rate of reaction is favoured by the bulkiness of the alkyl substituent • Controlled by the stability of the carbocation intermediate • Alkyl halides which cannot form stable carbocations will not react via SN1 Slide 15 of 29 MPharm PHA111 Functional Group Chemistry 15 WEEK 11 Racemisation of Stereocentres Substitution of a chiral alkyl halide results in racemic mixtures of products • 1:1 mixtures of the two possible stereoisomers • Remember that carbocationsadopt trigonal planar geometry • Nucleophile can approach from either face Slide 16 of 29 MPharm PHA111 Functional Group Chemistry 16 WEEK 11 Characteristics of the SN1 Reaction Tertiary alkyl halides are the most reactive by this mechanism • • Stability of the carbocation Hyperconjugation Allylic and benzylic carbocation intermediates are stabilised by delocalisation of the charge (resonance) Primary allylic and benzylic halides are also more reactive in the SN2 mechanism Slide 17 of 29 MPharm PHA111 Functional Group Chemistry 17 WEEK 11 A Note: Vinyl and Aryl Halides Vinyl and aryl halides do not react via SN1 or SN2 reaction mechanisms Slide 18 of 29 MPharm PHA111 Functional Group Chemistry 18 WEEK 11 Nucleophilic Substitution Examples in Biology/Pharmacy Methylation for synthesis of adrenaline Slide 19 of 29 MPharm PHA111 Functional Group Chemistry Nitrogen Mustards • treatment of cancer • DNA crosslinking 19 WEEK 11 Slide 20 of 29 MPharm SN1 vs SN2 Summary PHA111 Functional Group Chemistry 20 WEEK 11 Amines: Occurrence 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 • Other physiological molecules ~70% of pharmaceuticals contain nitrogen Slide 21 of 29 MPharm PHA111 Functional Group Chemistry 21 WEEK 11 Synthesis of Amines • Ammonia and other amines are good nucleophiles • Primary, secondary and tertiary amines all have similar reactivity • In theory, can synthesise alkyl amines via nucleophilic substitution reactions with relevant alkyl halide (e.g. MeI) • • Monoalkylatedproducts usually react further to yield a mixture of products –a synthetic challenge to overcome Other synthetic methods do exist to synthesise monoalkylatedproducts which circumvent this issue Slide 22 of 29 MPharm PHA111 Functional Group Chemistry 22 WEEK 11 Synthesis of Amines Reduction of nitriles and amides yield primary amines • Compare to reduction of esters • Reduction of imines yield secondary and tertiary amines (not shown) Slide 23 of 29 MPharm PHA111 Functional Group Chemistry 23 WEEK 11 Reactions with Carboxylic Acid Derivatives • Primary or secondary amines react with acid chlorides to produce amides • Primary or secondary amines react with sulfonyl chlorides to produce sulphonamides • Sulfa drugs: antibacterial agents • NB: These are not SN2 reactions Slide 24 of 29 MPharm PHA111 Functional Group Chemistry 24 WEEK 11 Amines –Structure and Bonding • Bonding in amines is similar to that in ammonia • • • • • • • • N is sp3 hybridised Lone pair of electrons in an sp3 hybrid orbital Tetrahedral geometry If only considering bonded atoms (and not the lone pair) shape is trigonal pyramidal C-N-C bond angles are ~109o High electrostatic potential at N Reactivity of the lone pair dominates properties of amines • Basic and nucleophilic Partial negative charge localised in the region of the lone pairs Slide 25 of 29 MPharm PHA111 Functional Group Chemistry WEEK 11 Amines - Classification Alkylamines – alkyl substituted Arylamines – aryl substituted Classified as: • 1o–Primary –RNH2 • 2o–Secondary –R2-NH • 3o–Tertiary –R3N Quaternary ammonium ions • A N atom with four attached groups is positively charged • When all substituents R are alkyl/aryl (not H) compounds are quaternary ammonium salts Slide 26 of 29 MPharm PHA111 Functional Group Chemistry WEEK 11 Amines – Hydrogen Bonding Amines can form hydrogen bonds • NH is less polar than OH • Weaker H-bonds • Lower boiling points compared with analogous alcohols • Difference in electronegativity: • O-H 1.4 • N-H 0.9 • Both H-bond acceptor and donor properties with 1o and 2o amines Slide 27 of 29 MPharm PHA111 Functional Group Chemistry WEEK 11 Amine Salts 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 • • • • Ionic solids with high m.p.s Soluble in water No ‘fishy’ odour Reversible • More soluble in water than the corresponding parent amine or ‘freebase’ • For this reason, amine drugs are often formulated as salts as they will readily dissolve in body fluids Slide 28 of 29 MPharm PHA111 Functional Group Chemistry WEEK 11 Acid/Base Properties of Amino Acids • In neutral solutions, carboxylic acid and amino groups are both ionised • Zwitterion – a dipolar ion • In acid solution, the carboxylic acid group is predominantly nonionised and the amino group predominantly ionised • In basic solutions, the reverse is true • An amino acid can never exist as an uncharged species Slide 29 of 29 MPharm PHA111 Functional Group Chemistry