W10 MPharm Programme PHA111 Functional Group Chemistry 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 ① receptor binding produces a therapeutic effect and design new medicines for specific purposes Understand how physiochemical properties affect ① 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 patiaa pointin - isoner.. ce Coor H2N 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 richt D o or & nucleophile 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: I art curuaro “Nucleus-loving” from Electron-rich – your curly arrow um 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 Y love pair electrons apodreadline = Slide 11 of 36 MPharm PHA111 Functional Group Chemistry WEEK 10 Electrophile carbon Electrophile: ↑ cation “Electron-loving” 11 Electron-poor – your curly arrow ends here! Typically has a positive charge (cation) or are polarisable = molecules, δ+ Polarisation by proximity can occur unusual m alkan 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 al resonance stable after they leave the substrate ~ ↳ can be stable charge in negative You will be required to write mechanisms involving general nucleophiles, electrophiles and leaving groups – practice! Standard abbreviations: Nu: or Nu- leave - stable E+ 9 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 I Two electron movement to B pair of = products Two-headed curly arrow radical HOMOLYSIS reaction mechanism Bond breaks such that each of the atoms retains one of the bonding electrons single-headed electrons ! * Do NOT miss 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 F 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 Institutions 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 X A 1 # initial reaction Ishould be expressed) => 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 - electro 00 zoneti 9 Yenzyme serine active site 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 eX) benzene 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 me Also known as ‘paraffins’ parum (too little) + affinis quantity General formula - CnH2n+2 pKa > 50 (exceptionally inert) unreactive (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 not moving 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 Alkane Weak London dispersion forces are the ↑ only intermolecular forces at play between substances where there is no permanent dipole (temporary dipoles #hydrophobic elections can occur) interactions moving area 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) chlorination Bromine (Br2) Bromination – 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 Ye absorbed, 1000s of molecules of CH3Cl are produced Chlorom Chlorine radical is said to be the chain carrier in propagation steps. Overall result is free-radical substitution exchange of H for ↓ side reactions 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 preformed I radicals 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 & more ( more stable ↑ The number of carbon atoms bonded to the carbon with the lone electron determines the kind of radical: most ↓ mosestable 3 C atoms – tertiary (3o) ↑ ↳ reaction stable tends to occur 2 C atoms – secondary (2o) the in most stable intermediate 1 C atom – primary (1o) 0 C atoms – methyl Alkyl groups are weakly electron donating due to hyperconjugation effect Y delocalization of electrons in a bond Istabilising Carbocations follow same pattern Slide 28 of 36 MPharm PHA111 Functional Group Chemistry WEEK 10 Hyperconjugation Hyperconjugation is a stabilising 17'08 interaction a Isharing Results from the interaction of the of ze- electrons in a σ-bond with an adjacent 1 unfilled p orbital or a π orbital Results in an extended molecular orbital that increases the stability of the system # 1 7 most adjacent on more available for hyperconjugation 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 textbook check ! Youtube Delocalisation of electrons prof or. dave Partial radicals residing over several atoms instead of just one. Slide 30 of 36 MPharm PHA111 Functional Group Chemistry  formal charge no or valence e r no or sonar no or ensnared e's PHAY0002: An Introduction to Organic Chemistry The formal charge on an atom can be calculated by adding up the number of electrons that ‘belong’ to each atom in the structure and comparing it to the number of valence electrons that the atom usually has. An atom contributes one electron to every covalent bond it makes. For the ‘top’ oxygen atom: It contributes one electron to each of the bonds making up the double bond with nitrogen. There are also four electrons in the two lone pairs. This gives a total of six electrons. Oxygen normally has six valence electrons (see Table 1) so the formal charge is zero (uncharged). For the ‘bottom’ oxygen atom: It contributes one electron to the covalent bond with nitrogen. There are also six electrons in the three lone pairs. This gives a total of seven electrons. Oxygen normally has six valence electrons so there is one extra electron (one extra negative charge) so the formal charge is –1. For the nitrogen atom: It forms a total of four covalent bonds, contributing one electron to each. There are no lone pairs of electrons. This gives a total of 4 electrons. Atomic nitrogen normally has 5 valence electrons so one has been lost. The formal charge is +1. oxygen has valence electrons hydrogen has 1 valence electron number of bonds = number of bonds = 1 unshared electrons = unshared electrons = 0 formal charge =o formal charge = 1 - 1 - 0 = 0 H O oxygen has valence electrons H C N 6 number of bonds = 1 carbon has 4 valence electrons H O unshared electrons = 6 number of bonds = 4 formal charge = unshared electrons = 0 I formal charge = 4 - 4 - 0 = 0 nitrogen has valence electrons s number of bonds = unshared electrons = formal charge = 1 to number of number of unshared Formal charge = number of valence electrons - - bonds electrons Study Questions Q1.6 Draw the structure of ozone (O3). Show all unshared electrons and calculate the formal charge on each atom. (Hint: ozone contains a chain of three oxygen atoms) Q1.7 Calculate the formal charge on each atom in nitric acid (HO-NO2). 1.9 Resonance Forms In the nitromethane example above, there is a double bond to one oxygen and a single bond to the other. How do we know which oxygen is which? Why did we draw the double bond to the ‘top’ oxygen? double bond here... the oxygen atoms are H O H O identical H C N or H C N... or here? resonance norms H O t o H O Page 11 neither are correct hybrid structure singe unchanging son cause erections aorocarised across an twee atone  do b ooh i PHAY0002: An Introduction to Organic Chemistry H Em Yes sts on n yc n c In reality, the two oxygen atoms are identical. The bond lengths and strengths of both of the N-O bonds are the same. Using the structures we have been drawing up to now, we cannot properly draw the structure of nitromethane on paper. Neither of the two Lewis structures for nitromethane is correct; the true structure is somewhere in between. The two individual Lewis structures for nitromethane are called resonance forms (or resonance contributors) and are indicated by a double-headed arrow between them. o ne Ea Q H Nitromethane is no different from any other molecule. It doesn’t jump back and forth between the two resonance forms. Nitromethane is a single, unchanging structure that is a hybrid of both resonance forms. The problem is drawing it on paper using the conventions we have described up until now. The electrons can be thought of being shared or delocalised across all three atoms, giving extra stability. This idea will become particularly important when we look at aromatic compounds like benzene. Study Question Q1.8 Draw resonance forms for ozone and nitric acid (Q1.6 and Q1.7 above). 1.10 How to Draw Organic Molecules Up to now we have been concentrating on Lewis structures, which are good for keeping track of electrons. Drawing out full Lewis structures showing all the bonds is time consuming, especially for very large molecules. There are a number of ways to draw organic molecules more quickly. To draw a molecule, you need to know its molecular formula, i.e. the number of atoms of each element that it contains. The molecular formula of propan-2-ol is C3H8O, but by itself this tells you nothing about its structure. You also need to know the order in which the atoms are connected to each other – the connectivity of the molecule. This information must also be available from any structural representation that we draw. The Lewis structure for propan-2-ol is shown below. Lewis sinecures are used beet tare time Moreover comme Catego connectivity Instead of drawing out all the covalent bonds in full, we can leave some or all of them out and write a condensed formula for the molecule. Subscripts are used to indicate the number of identical groups attached to a particular atom. condensed formula at aecomare exoxy ethane on azo crate or even car Cao Page 12 proper z or WEEK 10 Resonance Contributors and Hybrids not real arrows El curly NBHM chemical tot mechanism It ME real - 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 carbo- cation ↓ ↓ electron density Slide 32 of 36 MPharm PHA111 Functional Group Chemistry WEEK 10 Resonance Used to describe electron/charge delocalisation determine the Istability rate o sp3 hybridised atoms cannot accept electrons via resonance Resonance structures only exist on paper Only representations of the extreme possibilities of e- location 26'00 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 * not sp3 unhybridized Atoms must be in the same plane p porbitals ‒ Overlap of p orbitals required & no ? unable to delocalize e- 2 since er cannot move er 03 Energy of the molecule is less than any of the contributing structures eX) Benzene electrons ‒ The most stable resonance form makes the greatest [ delocalize along contribution to the overall structure ring the ‒ Charge separation decreases stability ‒ The more covalent bonds, the more stable the resonance form Slide 34 of 36 MPharm PHA111 Functional Group Chemistry WEEK olttlotl ! 10 Resonance Stabilisation of Radicals spa spadyspa" spr breaking accentsond 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 10 -0 36 Slide 36 of 36 MPharm PHA111 Functional Group 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) pophili -a [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 w - opposite Interconversion can be same brought about by treating with a strong acid, thermally or by UV light Cis isomers are less stable not gonna occur than trans isomers biologically there's enzyme Glunlessof Strain between the two loads ↓ E 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 ↳ light is being observed 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 elimination in free E ~ net ? Slide 7 of 31 MPharm PHA111 Functional Group Chemistry WEEK 10 Alkenes: Addition Reactions Involves ELECTROPHILIC ADDITION including double bond Has greater electron density than single bonds ~ electrona a Electrons in p bond are more accessible to approaching reactants Nucleophilic and reacts with electrophile Electron movement from double R o electricity partial 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 * summary 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"Halogen Addition of HCl, HBr or HI Symmetrical alkenes can only give one product Two step process ) H + 1+ pulling St 8 electrons - I to itself ⑪ 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 How * many Stability of carbocation controls outcome of reaction subs attached to C 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 - empty and C-H σ bonds on or partially charged neighbouring carbons Inductive effect very electro (+ ) ↓ 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 U #) of water Follows Markovnikov Addition & no suitable Reverse of dehydration of alcohol leaving G Acid catalysed (H2O is protonated) - & Use very dilute solutions of H2SO4 to drive equilibrium toward - protonating hydration (catalysing) Le Chatelier’s Principle ↓ & neutral Stable 16 Slide 16 of 31 MPharm PHA111 Functional Group Chemistry WEEK 10 Alkenes : Anti-Markovnikov Addition In the presence of peroxides, HBr adds to like to an alkene to form the “anti-Markovnikov” break & create radicals product by a radical mechanism only HBr has the appropriate bond energy Br HCl bond is too strong radical O HI bond tends to break heterolytically to. perox secondly form ions T offet oT7 proton E Intitiation, Propagation, Termination stat pick-up 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 induce polariset ↓ fit - 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 I metal used - commonly O rreactive ↓ double bonds => lose reactivity of rnq Slide 19 of 31 MPharm PHA111 Functional Group Chemistry WEEK 10 Alkenes: Versatile Reagents Markovnikov' ex] Br , a Slide 20 of 31 MPharm PHA111 Functional Group Chemistry WEEK 10 Alkynes: Structure W = 1 Alkenes - electrophi addition. significantly not good more acidic acid) than alkenes 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 pulth basic ~ 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 V Alkylation of Terminal Alkynes commonly used – Nucleophilic Substitution - in drug synthesis leaving group ~ 25 Slide 25 of 31 MPharm PHA111 Functional Group Chemistry WEEK 10 Alkynes: Addition of HX Twice 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 throughmechanism is 190 Addition of H2O –Same mechanism as for addition to alkenes alcohol –Acid catalysed * # On - * Reading Gene ↑ ketoend TAUTOMERIZATION leads to KETONE FORMATION # tautomerization 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 End 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 R R 1 INTERNAL ALKYNES H C C H H H ALKANES Slide 31 of 31 MPharm PHA111 Functional Group 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 S Reactivity controlled by electron rich oxygen atom - diphatic dcohol (weekly acidia pKa range = 15.5-18.0 (phenols ~10) Sub-classified as follows: = cromatic alcohol 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 Halogens (the electron withdrawing) - further stabilise the result in Phenol is 100 million times more acidic than cyclohexanol - ve charge occurs as of deprotonation Negative charge stabilised by resonance result a 4 Slide 4 of 25 MPharm PHA111 Functional Group Chemistry WEEK 11 Alcohols: pKa logka preferred when measure Alcohol Structure Ka = acid dissociation pKa # ocidity no ( 2stangible constant Methanol CH3OH 3.2 x 10-16 15.5 Ethanol CH3CH2OH 1.3 x 10-16 15.9 conjugate base 2-chloroethanol ClCH2CH2OH 5.0 x 10-15 14.3 of 2-chloroethand - lost the proton of the-or 2,2,2- Cl3CH2OH 6.3 x 10-13 12.2 V - remainder of group trichloroethanol molecule Il much better Isopropyl alcohol (CH3)2CHOH 3.2 x 10-17 16.5 stabilising resulting re - - t-Butyl alcohol (CH3)3COH 1.0 x 10-18 18.0 change mone-donating 4pk 4e-withdrawing group Cyclohexanol C6H11OH - 1.0 x destabilise 10-18 18.0 group-happy of to pull some deprotonation - Phenol C6H5OH 1.0 x 10-10 10.0 e-density prenoxide Towards Itself [ resonance Comparison with other acids - stabilised ↓ Ka election & withdrawing acidity + Water H2O 1.8 x 10-16 15.7substituents I = basic acohol's pka Acetic acid CH3COOH 1.6 x 10-5 4.8 Hydrochloric acid HCl 1.6 x 102 -2.2 - 7 Isolvent dependent) 5 Slide 5 of 25 MPharm PHA111 Functional Group Chemistry WEEK 11 Alcohols: Physical Properties Similar increases in melting point/boiling point across the be homologous series directly - can compared Unusually high boiling points due to H-bonding between molecules Small alcohols are miscible with ↓ as water, but solubility decreases the size of the alkyl group 3 increases↑ increasing the = amount of hydrophobic region on that molecule Like dissolves like polar-polar (solvent non-polar-non-polar (solvent 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 1) Hydrolysis of alkyl halides 2) Nucleophilic substitution reactions n) Reduction of carbonyl compounds E.g. aldehydes, ketones, carboxylic acids, esters & reduced to the corresponding acohol 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 * need to be able to Aldehydes, ketones, esters, carboxylic acids identify ! difference 1 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 um 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 electrophilic /addition (Hydration > - acohol > primary - reduce using oxidised NaBH4/LiAN4 acohol - primary/ secondary 10 Slide 10 of 25 MPharm PHA111 Functional Group Chemistry WEEK 11 Alcohols: Reactivity Completely burn in O2 combustion 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 HBr/HC 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 ~ push the equilibrium further towards ↓ the energy required product - Ester Acid catalysed to get the reaction ⑦ H2SO4is a source of H+ and a dehydrating um agent Reversible reaction Series of equilibria * le chatelier's principle Aqueous acid hydrolyses esters to by removing water from right-side carboxylic acids of the equation 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 = adehyde = Ketore 13 Slide 13 of 25 MPharm PHA111 Functional Group Chemistry WEEK 11 Biological Oxidation of Alcohols Two step process within the u 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) Mdehyde -dcohol (treat dcoholic urgent option 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 halide Alkyl halide - # We look at the mechanistic implications later on…. u 15 Slide 15 of 25 MPharm PHA111 Functional Group Chemistry WEEK 11 * Phenols Very different properties to aliphatic alcohols Phenols are planar (f(ct) C-O bond distance is 136 pm, which is slightly shorter than that of CH3OH (142 pm) Unusual H-bonding 7 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 - unusual compared to oddity diphatic alcohols 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 ~ WHY Pheno is much more acidic not in a fixed location o - delocalise around the ring resonance ~ contributor 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. S similar to adrendine 18 Slide 18 of 25 MPharm PHA111 Functional Group Chemistry WEEK 11 Haloalkanes: General Unsaturated or saturated compoundsayhalogens 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 Yu Can be attacked by a nucleophile Halogen is the leaving group which takes an electron pair C-Xbond attached to cromatic system 19 Slide 19 of 25 MPharm PHA111 Functional Group Chemistry WEEK 11 Haloalkanes: Anaesthetics Diethyl Ether (ether) first used in late 1800s (dentistry) I Accumulates in lipid membrane of nerve cells and interferes with transmission of nerve impulses > - reducing of pain amount Very flammable, low flash point un ↓flash or set fire on a 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 m 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 ex) Pichloromethane /Holodkone solvent) ~ - very heavy due to its greater density relative to the corresponding akones 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 partition with => CHX3 water 1.483 2.890 4.008 = (water) not miscible CX4 1.594 3.273 4.23 Di- and polyhalogenated alkanes are more 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 o o - 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) m 2 = Both nucleophile and substrate are involved in the characteristic step (i.e. reaction is bimolecular) un 24 Slide 24 of 25 MPharm PHA111 Functional Group Chemistry  Further Reading/References 25 Slide 25 of 25 MPharm PHA111 Functional Group Chemistry WEEK 11 MPharm Programme PHA111 Functional Group Chemistry 4 Dr. Stephanie Myers Senior Lecturer in Medicinal Chemistry Dale 1.21 [email protected] Telephone: 0191 5152760 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 2 Slide 2 of 29 MPharm PHA111 Functional Group Chemistry 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 strong/week 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 lawum - kinetics Depends which reagents are involved in the rate determining step ~ etection ↳ rate constant 3 Slide 3 of 29 MPharm PHA111 Functional Group Chemistry WEEK 11 Three Experimental Evidences Support an SN2 Mechanism 1. The rate of reaction us dependent on the concentration of both the haloalkane and Idkylhdidal the nucleophile * 2. The rate of reaction with a given ↑ size nucleophile decreases with increasing of the haloalkane (p + ) s + + 3. If a chiral alkyl halide is used, the chirality of the substituted product is inverted relative to the starting material 4 Slide 4 of 29 MPharm PHA111 Functional Group Chemistry WEEK 11 Size of the Alkyl Halide The rate of reaction with a given nucleophile decreases with increasing size of the haloalkane slower rapid 5 Slide 5 of 29 MPharm PHA111 Functional Group Chemistry 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 Steri (bulk) i how easy for the is It nucleophile to approach that carbon centre ex)bulky substituent -Partialy Surrounds electros carbon Partialare v need diff. that ↓ tor - mount of sterically activation hindered energy = nucleophile cannot access to the easily 6 Slide 6 of 29 MPharm PHA111 Functional Group Chemistry WEEK 11 SN2 Transition State Transition state / * The TS of an SN2 reaction has a planar (flat) arrangement of the carbon atom and the remaining three groups 7 Slide 7 of 29 MPharm PHA111 Functional Group Chemistry WEE