Week 10 Functional Group Chemistry 1 PDF

WEEK 10 MPharm Programme PHA111 Functional Group Chemistry 1 Dr. Stephanie Myers Senior Lecturer in Medicinal Chemistry...

WEEK 10 MPharm Programme PHA111 Functional Group Chemistry 1 Dr. Stephanie Myers Senior Lecturer in Medicinal Chemistry Dale 1.21 [email protected] Telephone: 0191 5152760 Slide 1 of 36 MPharm PHA111 Functional Group Chemistry WEEK 10 Learning Objectives 1. Appreciate why functional group chemistry is important for students of pharmacy 2. Define a wide range of mechanistic terminologies which will help you deduce and explain reaction mechanisms in this course 3. Identify the nucleophile, electrophile and determine whether a leaving group is present in complex organic molecules 4. Begin to be able to identify different functional groups in drug molecules and their properties Focus on alkanes in this lecture 5. Use accurate curly arrows to denote bond making/breaking processes Focus on alkane chemistry in this lecture 6. Explain product distribution patterns observed with reference to radical stability via hyperconjugation and/or resonance stabilisation 2 Slide 2 of 36 MPharm PHA111 Functional Group Chemistry WEEK 10 Functional Groups Understanding the chemistry of functional groups enables us to develop ability to: Consider chemical structure Deduce properties of drugs such as: Ionisation Solubility (lipid vs. aqueous) Absorption, Distribution, Metabolism, Excretion (ADME) 3 Slide 3 of 36 MPharm PHA111 Functional Group Chemistry WEEK 10 Functional Groups Understand how receptor binding produces a therapeutic effect and design new medicines for specific purposes Understand how physiochemical properties affect analytical choices 4 Slide 4 of 36 MPharm PHA111 Functional Group Chemistry WEEK 10 What is a Functional Group? Most drugs are simple organic molecules which are composed of two parts: HYDROCARBON PART that is usually unreactive FUNCTIONAL GROUP (FG) where most of the reactions/interactions of the molecule occur Molecules having the same functional group generally have: SIMILAR PROPERTIES CHARACTERISTIC REACTIVITIES 5 Slide 5 of 36 MPharm PHA111 Functional Group Chemistry WEEK 10 Chemical Similarity 6 Slide 6 of 36 MPharm PHA111 Functional Group Chemistry WEEK 10 What is a Functional Group? 7 Slide 7 of 36 MPharm PHA111 Functional Group Chemistry WEEK 10 What is a Functional Group? 8 Slide 8 of 36 MPharm PHA111 Functional Group Chemistry WEEK 10 3D Representations Remember that sp3 hybridised carbon atoms adopt a tetrahedral shape They are not flat but adopt a three-dimensional structure Represented using wedged and hashed bonds Wedge – bond is pointing towards us Hash – bond is pointing away from us The plain bonds are in the plane of the screen Particularly important when we are looking at chiral molecules Chiral centre – carbon atom with four different groups attached 9 Slide 9 of 36 MPharm PHA111 Functional Group Chemistry WEEK 10 Reactivity and Reaction Mechanisms A mechanism is a detailed set-by-step description of a chemical process in which: REACTANTS →PRODUCTS Sequence of bond-making and bond-breaking steps involving the movement of electrons Initially can be classified in two ways: IONIC or POLAR – movement of two electrons in turn RADICAL – movement of one electron in turn 10 Slide 10 of 36 MPharm PHA111 Functional Group Chemistry WEEK 10 Nucleophile Nucleophile: “Nucleus-loving” Electron-rich – your curly arrow starts here! Atom or molecule that has a pair of electrons to share Typically has a negative charge (anion) or a lone pair of electrons Double bonds e.g. alkenes, can act as nucleophiles Slide 11 of 36 MPharm PHA111 Functional Group Chemistry WEEK 10 Electrophile Electrophile: “Electron-loving” Electron-poor – your curly arrow ends here! Typically has a positive charge (cation) or are polarisable molecules, δ+ Polarisation by proximity can occur Slide 12 of 36 MPharm PHA111 Functional Group Chemistry WEEK 10 Leaving Groups Terminology used for ions or neutral molecules that are displaced from a reactant as part of a mechanistic sequence Normally a consequence of a nucleophile (Nu) attacking an electrophile (E) where the electrophile carries a suitable leaving group (L) Good leaving groups are those that form stable ions or neutral molecules after they leave the substrate You will be required to write mechanisms involving general nucleophiles, electrophiles and leaving groups – practice! Standard abbreviations: Nu: or Nu- E+ L: or L- 13 Slide 13 of 36 MPharm PHA111 Functional Group Chemistry WEEK 10 Bond Cleavage HETEROLYSIS Bond breaks such that both of the electrons stay with one of the atoms Two electron movement to B Two-headed curly arrow HOMOLYSIS Bond breaks such that each of the atoms retains one of the bonding electrons One electron movement to both A and B One-headed curly arrows Slide 14 of 36 MPharm PHA111 Functional Group Chemistry WEEK 10 Curly Arrows – Polar Mechanisms Double headed arrow denotes movement of two electrons Arrow placement is very important! ELECTRON ELECTRON RICH CENTRE POOR CENTRE Negative Charge Positive Charge Lone Pair Empty p Orbital Electron Rich Bond δ+ end of polarised bond F N H C O Slide 15 of 36 MPharm PHA111 Functional Group Chemistry WEEK 10 Curly Arrows – Radical Mechanisms Single headed arrow denotes movement of one electron RADICAL RADICAL Note that to form a bond (made up of 2 electrons) two radicals must each donate one electron Similarly, to break a bond via a radical mechanism, each atom at either end must receive one electron (homolysis) 16 Slide 16 of 36 MPharm PHA111 Functional Group Chemistry WEEK 10 Transition States and Intermediates Mechanisms can include a number of predicted structures, charged species or radicals which lie on the pathway Diagrams which can represent energy change over time are a good way to demonstrate the involvement of reactants to products The energy difference between reactants and products is the standard free energy change 17 Slide 17 of 36 MPharm PHA111 Functional Group Chemistry WEEK 10 Transition States and Intermediates The energy difference between the starting material and the transition state is termed the activation energy The high energy peak or peaks are referred to as transition states (or activated complex) If there is an energy minimum between two transition states then this represents there is an intermediate structure in the pathway 18 Slide 18 of 36 MPharm PHA111 Functional Group Chemistry WEEK 10 Why Study Mechanisms? Beneficial as a pharmacist to have a good understanding about how drugs are made – a small number of pharmacists undertake a PhD in medicinal chemistry Some drugs work by covalently binding to their biological target – involves a chemical mechanism Some metabolic processes involve chemical mechanisms – inside our body! Understanding the mechanism involved helps us predict metabolic stability of drugs Drug degradation processes occur via chemical reactions. Understanding their mechanisms can help us improve stability 19 Slide 19 of 36 MPharm PHA111 Functional Group Chemistry WEEK 10 Penicillins MOA Amoxycillin in enzyme active site Example of a covalent inhibitor Reaction starts at electron rich alcohol (Serine) Electrons move towards electron poor carbon (lactam) as shown by curly arrow Conversion of 3o cyclic amide (lactam) to ester and 2o amine Resulting ester is stable to hydrolysis 20 Slide 20 of 36 MPharm PHA111 Functional Group Chemistry WEEK 10 Hydrocarbon Compounds 21 Slide 21 of 36 MPharm PHA111 Functional Group Chemistry WEEK 10 Alkanes Saturated compounds Contain only single bonds No double or triple bonds Contain only C-C and C-H bonds Also known as ‘paraffins’ parum (too little) + affinis General formula - CnH2n+2 pKa > 50 (exceptionally inert) (affinity) due to their [HCl pKa= -7, H2O pKa= 15.7] unreactivity React poorly with ionic or polar substances Strong σ bonds Inert to acids and bases Virtually insoluble in water Isolated from petroleum by distillation More complex alkanes can be made through hydrogenation of alkenes or alkynes Slide 22 of 36 MPharm PHA111 Functional Group Chemistry WEEK 10 Alkanes: Physical Properties Melting points and boiling points of alkanes generally increase with molecular weight and with the length of the main carbon chain For a homologous series At standard conditions: CH4 to C4H10 gaseous C5H12 to C17H36 liquids C18H38 and above solids Weak London dispersion forces are the only intermolecular forces at play between substances where there is no permanent dipole (temporary dipoles can occur) Slide 23 of 36 MPharm PHA111 Functional Group Chemistry WEEK 10 Alkanes: Reactivity Generally very unreactive Combustion – Burn in a flame producing CO2, H2O and heat Halogenation – Alkanes do react with: Chlorine (Cl2) Bromine (Br2) – Rapid reaction involving radicals – Only takes place at high temperatures (Δ) or in the presence of high energy light (hν) Slide 24 of 36 MPharm PHA111 Functional Group Chemistry WEEK 10 Alkanes: Halogenation Halogenation of alkanes usually proceeds via a radical mechanism Radical reactions are characterised by three main steps: Initiation – formation of radical Light induced formation of chlorine radicals through homolysis from neutral chlorine Propagation – One radical is used to generate another radical The chlorine radical can now abstract a hydrogen from another neutral molecule CH4 producing a methyl radical Termination – The combination of two radicals to produce a neutral species The methyl radical can combine with the chlorine radical to give a neutral chloromethane Slide 25 of 36 MPharm PHA111 Functional Group Chemistry WEEK 10 Alkanes: Halogenation For each photon of light that is absorbed, 1000s of molecules of CH3Cl are produced Chlorine radical is said to be the chain carrier in propagation steps. Overall result is free-radical substitution exchange of H for Cl Slide 26 of 36 MPharm PHA111 Functional Group Chemistry WEEK 10 Radical Stability What factors determine substituted product distribution? Probability? C4H10 Predicted substitution at CH3 60%, CH2 40% Stability of Radicals formed as intermediates Slide 27 of 36 MPharm PHA111 Functional Group Chemistry WEEK 10 Radical Stability Distribution patterns of product determined by the stability of the intermediate radical The number of carbon atoms bonded to the carbon with the lone electron determines the kind of radical: 3 C atoms – tertiary (3o) 2 C atoms – secondary (2o) 1 C atom – primary (1o) 0 C atoms – methyl Alkyl groups are weakly electron donating due to hyperconjugation effect Carbocations follow same pattern Slide 28 of 36 MPharm PHA111 Functional Group Chemistry WEEK 10 Hyperconjugation Hyperconjugation is a stabilising interaction Results from the interaction of the electrons in a σ-bond with an adjacent unfilled p orbital or a π orbital Results in an extended molecular orbital that increases the stability of the system Slide 29 of 36 MPharm PHA111 Functional Group Chemistry WEEK 10 Radical Stability Two radicals more stable than would be expected are: Benzyl radical Allyl radical They are unusually stable due to Resonance Delocalisation of electrons Partial radicals residing over several atoms instead of just one. Slide 30 of 36 MPharm PHA111 Functional Group Chemistry WEEK 10 Resonance Contributors and Hybrids 31 Slide 31 of 36 MPharm PHA111 Functional Group Chemistry WEEK 10 Resonance Structures Being able to draw and rationalise resonance structures is an integral part of drawing and understanding reaction mechanisms Resonance forms are not isomers or different compounds Represent using the double-headed resonance arrows Slide 32 of 36 MPharm PHA111 Functional Group Chemistry WEEK 10 Resonance Used to describe electron/charge delocalisation sp3 hybridised atoms cannot accept electrons via resonance Resonance structures only exist on paper Only representations of the extreme possibilities of e- location Only π electrons and lone-pair electrons/radicals are moved, nuclei remain in the same position The total number of electrons does not change 33 Slide 33 of 36 MPharm PHA111 Functional Group Chemistry WEEK 10 Resonance Structures The same number of paired and unpaired electrons exist in each resonance form Atoms must be in the same plane ‒ Overlap of p orbitals required Energy of the molecule is less than any of the contributing structures ‒ The most stable resonance form makes the greatest contribution to the overall structure ‒ Charge separation decreases stability ‒ The more covalent bonds, the more stable the resonance form Slide 34 of 36 MPharm PHA111 Functional Group Chemistry WEEK 10 Resonance Stabilisation of Radicals Note the use of a double-headed arrow – not equilibrium! Slide 35 of 36 MPharm PHA111 Functional Group Chemistry WEEK 10 Stability of Drugs - AutoOxidation Oxidation – radical process – increase in the number of bonds to oxygen – a decrease in the number of bonds to hydrogen – loss of electrons Auto-oxidation – Leads to drug degradation under mild conditions light heat some metal ions peroxides 36 Slide 36 of 36 MPharm PHA111 Functional Group Chemistry