MPharm Programme PHA111 Functional Group Chemistry 2 PDF

WEEK 10 MPharm Programme PHA111 Functional Group Chemistry 2 Dr. Stephanie Myers Senior Lecturer in Medicinal Chemistry...

WEEK 10 MPharm Programme PHA111 Functional Group Chemistry 2 Dr. Stephanie Myers Senior Lecturer in Medicinal Chemistry Dale 1.21 [email protected] Telephone: 0191 5152760 Slide 1 of 31 MPharm PHA111 Functional Group Chemistry WEEK 10 Learning Objectives 1. Begin to be able to identify different functional groups in drug molecules and their properties Focus on alkenes/alkynes in this lecture 2. Use accurate curly arrows to denote bond making/breaking processes Focus on alkene chemistry in this lecture 3. Demonstrate understanding of the reactivity of alkenes/alkynes giving specific example reactions and their mechanisms Electrophilic addition Hydrohalogenation Hydration Halogenation Hydrogenation 4. Explain the regioselectivity of electrophilic addition reactions with reference to Markovnikov’s rule and carbocation/radical stability and predict product formation based on these principles 2 Slide 2 of 31 MPharm PHA111 Functional Group Chemistry WEEK 10 Alkenes Unsaturated Compounds Contain C-C double bonds (sp2 hybridised carbons) Contain only C-C and C-H bonds Contain a s bond and a weaker π bond Reactivity controlled by electron rich C-C double bond Double bond acts as nucleophile (electron rich) More substituted alkenes are more stable - hyperconjugation Slide 3 of 31 MPharm PHA111 Functional Group Chemistry WEEK 10 Alkenes Slightly POLAR p bond is polarisable, so instantaneous dipole- dipole interactions occur Alkyl groups are electron-donating toward the p bond, so may have a small dipole moment A bond between an sp2 carbon and an sp3 carbon is somewhat stronger than a bond between two sp3 carbons General formula - CnH2n pKa > 44 (exceptionally inert) [HCl pKa= -7, H2O pKa= 15.7, alkanes pKa > 50] Alkenes have low boiling points which generally increase with molecular weight and with the length of the main carbon chain Branched alkenes have lower boiling points Virtually insoluble in water Slide 4 of 31 MPharm PHA111 Functional Group Chemistry WEEK 10 Alkenes: Isomers Barrier to rotation with C=C Interconversion does not occur spontaneously Interconversion can be brought about by treating with a strong acid, thermally or by UV light Cis isomers are less stable than trans isomers Strain between the two larger substituents on the same side of the double- bond or Acid cat. Slide 5 of 31 MPharm PHA111 Functional Group Chemistry WEEK 10 Alkenes: Isomers and Vision Only cis-retinal fits into and binds with a receptor site of opsin Visible light is absorbed by rhodopsin causing isomerisation The neurons of the optic nerve fire producing a visual image 6 Slide 6 of 31 MPharm PHA111 Functional Group Chemistry WEEK 10 Alkenes: Reactivity Much more reactive than alkanes Preparation Cracking: industrial process Elimination: Dehydrohalogenation Dehydration Slide 7 of 31 MPharm PHA111 Functional Group Chemistry WEEK 10 Alkenes: Addition Reactions Involves ELECTROPHILIC ADDITION Has greater electron density than single bonds Electrons in p bond are more accessible to approaching reactants Nucleophilic and reacts with electrophile Electron movement from double bond (weaker π bond) to electrophile (E+ or δ+) Addition reactions can either be: HOMOLYTIC (involves radicals) HETEROLYTIC (involves cations) Slide 8 of 31 MPharm PHA111 Functional Group Chemistry WEEK 10 Alkenes: Reactivity Slide 9 of 31 MPharm PHA111 Functional Group Chemistry WEEK 10 Reactivity of C=C Double Bond Electrophilic addition Electrons in π bond are loosely held Step 1: π electrons attack the electrophile (E+, δ+ or E.) Carbocation intermediate (HETEROLYTIC cleavage) Radical intermediate (HOMOLYTIC cleavage) Step 2: Nucleophile (Nu-, Nu.) adds to the carbocation/radical Net result is ADDITION to the double bond Slide 10 of 31 MPharm PHA111 Functional Group Chemistry WEEK 10 Alkenes: Addition of HX Addition of HCl, HBr or HI Symmetrical alkenes can only give one product Two step process Slide 11 of 31 MPharm PHA111 Functional Group Chemistry WEEK 10 Alkenes: Addition of HX Asymmetric alkenes What is the product? Why is that product formed? Carbocation formation is the Rate Limiting Step Stability of carbocation controls outcome of reaction Slide 12 of 31 MPharm PHA111 Functional Group Chemistry WEEK 10 Alkenes: Markovnikov’s Rule Reaction proceeds via the most stable carbocation In an electrophilic addition to an alkene, the The proton of an acid (H-X) adds to the electrophile (E+) adds in sp2 carbon in the double bond that is such a way as to form the bonded to the greater number of most stable intermediate hydrogens The electrophile (E+) adds to the sp2 carbon in the double bond that is the most substituted HCl, HBr, and HI add to alkenes to form Markovnikov products (in the absence of light or peroxides) In a REGIOSELECTIVE reaction, one constitutional isomer is the major, or the only, product Slide 13 of 31 MPharm PHA111 Functional Group Chemistry WEEK 10 Carbocation Stability Outcome of product determined by the stability of the intermediate carbocation Trivalent carbon is sp2 hybridised and has a vacant p orbital perpendicular to the plane of the carbon The number of carbon atoms bonded to the carbocation determines the kind of carbocation 3 C atoms – Tertiary (3o) 2 C atoms – Secondary (2o) 1 C atom – Primary (1o) 0 C atoms – Methyl Slide 14 of 31 MPharm PHA111 Functional Group Chemistry WEEK 10 Carbocation Stability Alkyl groups are weakly electron donating Hyperconjugation stabilising interaction between a p orbital and C-H σ bonds on neighbouring carbons Inductive effect Decreases concentration of positive charge on C+ Carbon radicals follow same pattern Slide 15 of 31 MPharm PHA111 Functional Group Chemistry WEEK 10 Alkenes: Hydration Follows Markovnikov Addition Reverse of dehydration of alcohol Acid catalysed (H2O is protonated) Use very dilute solutions of H2SO4 to drive equilibrium toward hydration Le Chatelier’s Principle 16 Slide 16 of 31 MPharm PHA111 Functional Group Chemistry WEEK 10 Alkenes : Anti-Markovnikov Addition In the presence of peroxides, HBr adds to an alkene to form the “anti-Markovnikov” product by a radical mechanism only HBr has the appropriate bond energy HCl bond is too strong HI bond tends to break heterolytically to form ions Intitiation, Propagation, Termination Bromine radical adds first Product is governed by the formation of the most stable carbon radical Refer to radical stability from FGC L1 Slide 17 of 31 MPharm PHA111 Functional Group Chemistry WEEK 10 Alkenes: Addition of Halogens Cl2, Br2, and sometimes I2 add to a double bond to form a vicinal dihalide Reaction is stereospecific – anti (or trans) addition of E+ to the starting alkene p electrons attack the bromine molecule Loss of bromide ion – formation of nucleophile Intermediate is a cyclic bromonium ion Halide ion approaches from side opposite the three-membered ring Forms a vicinal dihalide Slide 18 of 31 MPharm PHA111 Functional Group Chemistry WEEK 10 Alkenes: Hydrogenation Formation of an alkane Syn (or Cis) addition so reaction is stereospecific Catalyst required, usually Pt, Pd, or Ni Slide 19 of 31 MPharm PHA111 Functional Group Chemistry WEEK 10 Alkenes: Versatile Reagents Slide 20 of 31 MPharm PHA111 Functional Group Chemistry WEEK 10 Alkynes: Structure Unsaturated Compounds Contain TRIPLE C-C bonds Internal/terminal triple bonds Contain 2 x weaker π bond Reactivity controlled by electron rich C-C triple bond Triple bond acts as nucleophile Very reactive Reactions are similar to alkenes General formula - CnH2n-2 pKa ~ 25 (terminal H); ~44 (adjacent CH2) [HCl pKa= -7, H2O pKa= 15.7] Virtually insoluble in water 21 Slide 21 of 31 MPharm PHA111 Functional Group Chemistry WEEK 10 Alkynes: Physical Properties Terminal Internal Stronger Van der Waals forces Internal alkenes/alkynes have higher BP than equal Mr terminal Slide 22 of 31 MPharm PHA111 Functional Group Chemistry WEEK 10 Alkynes: Relative Acidity pKa sp3 H3C H 43 INCREASING H H INCREASING s-ORBITAL sp2 C C 37 H H ACIDITY CHARACTER sp H C C H 25 Slide 23 of 31 MPharm PHA111 Functional Group Chemistry WEEK 10 Alkynes: Reactivity Completely burn in O2 Alkynes are less reactive than alkenes Very similar reactions to alkenes H-X addition – (with/without peroxides) X-X Addition (Br2, Cl2) H-H Addition (hydrogenation) H-OH Addition (hydration) Various reactions can often be stopped at the monoaddition stage if one molar equivalent of reagent is used Follows Markovnivov Rule Alkylation of terminal alkynes Slide 24 of 31 MPharm PHA111 Functional Group Chemistry WEEK 10 Alkylation of Terminal Alkynes Alkylation of Terminal Alkynes – Nucleophilic Substitution 25 Slide 25 of 31 MPharm PHA111 Functional Group Chemistry WEEK 10 Alkynes: Addition of HX Sequential addition of H-X (2 eq. needed) Follows Markovnikov Rule – Vinylic carbocations involved in 1st step – Can be primary or secondary Most stable carbocation formed 26 Slide 26 of 31 MPharm PHA111 Functional Group Chemistry WEEK 10 Alkynes: Addition Reactions Anti-Markovnikov H-Br addition possible –Requires peroxide as a radical initiator Halogenation –Same mechanism as for addition to alkenes 27 Slide 27 of 31 MPharm PHA111 Functional Group Chemistry WEEK 10 Alkynes: Anti-Markovnikov Addition Anti-Markovnikov addition only occurs under very specific conditions HBr as the nucleophile Radical initiator present e.g. H2O2 28 Slide 28 of 31 MPharm PHA111 Functional Group Chemistry WEEK 10 Alkynes: Hydration Addition of H2O –Same mechanism as for addition to alkenes –Acid catalysed TAUTOMERIZATION leads to KETONE FORMATION More complicated alkynes give several ketone products as several equally stable intermediates are formed Enols are initially formed which tautomerise to the more stable ketones 29 Slide 29 of 31 MPharm PHA111 Functional Group Chemistry WEEK 10 Alkynes: Hydrogenation Syn (cis) addition same as alkene with Pt/C/H2 ALKYNE → ALKENE→ ALKANE does not stop Reaction can be stopped at alkene with a ‘poisoned’ partially deactivated catalyst – Lindlar catalyst Trans (anti) addition of hydrogen is possible Radical mechanism 30 Slide 30 of 31 MPharm PHA111 Functional Group Chemistry WEEK 10 Alkynes: Versatile Reagents GEMINAL DIHALOALKANES X H GEMINAL R C C H DIHALOALKANES X H KETONES H X R R C C H R1 H-X O H X H H H-X Peroxide R H C C X H R X R H C C C C H H HO R1 H-X ENOLS H-OH H-X Peroxide R C C H X-X R X X-X X X R H C C or C C R C C R1 H R1 Na/NH3 R C C R1 X R1 X X TRANS-ALKENES NaNH 2 TETRAHALOALKANES Lindlar Catalyst H-H R R1 H-H C C R C C Na H H R R1 C C ACETYLIDES CIS-ALKENES H H R1 X H-H R C C R1 1 INTERNAL R R ALKYNES H C C H H H ALKANES Slide 31 of 31 MPharm PHA111 Functional Group Chemistry