topic 2: properties of molecules (organics)

The chemicals of life 

Living systems use and produce a wide range of chemicals 

• Simple chemicals like water,carbon dioxide, salt 

• Highly complex molecules like proteins, nucleic acids and other natural products 

The majority are organic compound 

• Historically, organic compounds were thought to be only produced by living organisms, but Wöhler’s generation of urea from inorganic components showed that production of organic compounds doesn’t need a ‘vital force’ 

•  It’s now well established that even non-natural organic molecules can be prepared synthetically 

Organic compounds 

• Molecules based on carbon covalently bonded to other elements – esp hydrogen, oxygen, and nitrogen 

• Carbon is able to form strong covalent bonds to a wide range of other elements, and link to a wide number of other atoms (carbon has 4 bonding regions) 

• Huge number of combinations of molecules are available: over 16 million organic compounds are known

Representing organic molecules 

• Name (systematic) 

• Common name 

• Molecular formula 

• Condensed structuralformula 

• Lewis structure 

• Full structural formula 

 Skeletal structures (aka stick/line diagrams) 

• Skeletal structures are the most efficient way to draw complex organic molecules 

• The hydrocarbon framework is shown as a series of lines 

• Clearly show functional groups (where reactions happen) 

• Functional groups may be drawn with non-bonding electron pairs (aka lonepairs) shown - optional 

Include non-bonding electrons if they are important for consideration of molecular shape or reaction mechanism, otherwise it’s up to you! 

drawing skeletal structures 

• The end of each line represents a carbon, unless a heteroatom is specified 

• Hydrogens on carbons are implied but not usually drawn, so as to make a neutral molecule with filled octets on each carbon, unless a charge or unpaired electron is shown 

• Hydrogens on functional groups must be included  

• Double and triple bonds are shown by two or three parallel lines 

• Bond angles in hydrocarbon frameworks are drawn roughly consistent with tetrahedral, trigonal planar and linear shapes 

abbreviations in skeletal structures

Me: methyl

Et: ethyl

iPr: isopropyl

tBu: tertairy- butyl

Ph: phenyl

CHO: aldehyde

CO2H: carboxylic acid

Skeletal structures and functional groups 

• Functional groups may be drawn with non- bonding electron pairs shown (or not) 

• include non-bonding electrons if important for consideration of shape or mechanism 

Functional Groups – Reactivity and Characterisation 

• Reactions occur primarily at functional groups, including biochemical reactions 

• Certain reactions are characteristic of particular functional groups 

Functional groups can be distinguished by spectroscopy: 

• infrared (IR) 

• Nuclear magnetic resonance (NMR) 

• Ultraviolet/visible (UV/vis) 

Functional groups can be distinguished by mass spectrometry

Identifying Carbonyl Functional Groups with IR spectroscopy

• The C=O bond of carbonyl and carboxyl functional groups has a stretching vibration in the region of 1800 – 1650 cm-1. 

• The exact wave number depends on what other groups are attached, i.e. which type of carbonyl/carboxyl FG it is. 

Isomers 

• Non-identical compounds with the same molecular formula are isomers 

• isomers typically exhibit different properties (physically, chemically and/or biologically) 

• Different functional groups react differently 

• Different order of atom connectivity leads to different shapes and physical natures – e.g. “packing” of  molecules in a solid or liquid affects melting point or boiling point, respectively=regioisomers 

• Different spatial arrangements of atoms lead to different 3D shapes 

The presence of different isomers is isomerism 

Classes of isomerism 

Isomerism 

• Same number and types of atoms 

Structural isomers 

• Different order of attachemen of atoms 

• Postitional/chain isomers 

• Fucntional group isomers 

Stereoisomers 

• Same order of attachment of atoms, different orientation 

• Confirmational isomers 

• Configurational isomers 

stereoisomerism 

Isomers that have the same order of connectivity of atoms but different spatial arrangements 

• Further divided into: 

Conformational isomers 

• differ in the spatial arrangement of groups around single bonds; usually interconvert rapidly 

Configurational isomers  

• differ in the spatial orientation around a cycloalkane, an alkene or a chiral centre; don’t interconvert readily 

• cis-/trans-, E-/Z-, R-/S-isomers 

• chirality = handedness 

Wedge and dashboard stereoboards 

• wedge: gets fatter towards us.  

• Hash: gets fatter away from us 

Representing 3d spatial arrangement on 2d plane 

cycloalkanes - stereoisomerism

Same connectivity, different three dimensional forms 

• Configurational isomers 

• Different arrangement about cycloalkane ring(different faces) 

• Named as cis- (same face) and trans- (opposite faces) 

alkenes - stereoisomerism

Same connectivity, different three dimensional forms 

• Configurational isomers 

• Different arrangements across double bond (different sides) 

• Named as cis- (or Z-) and trans- (or E-) 

naming Typically uses longest chain, if group cis to longest chain: is cis and vice versa.  

Ambigious method however, need better way 

CIP method of naming stereoisomers 

a robust naming system for stereoisomers 

• uses the atomic number to define the priority of each substituent 

• describes the relative spatial positions of the substituents systematically 

Step 1: Rank the atom directly attached to each carbon of interest based on atomic number 

• Highest atomic number is highest priority 

• Lowest atomic number is lowest priority 

Step 2: If atoms are the same, look at their substituents and rank the next atoms out 

• Calculate based on the first point of difference 

Step 3: For an alkene, compare the relative spatial positions of the highest ranked substituents at each end of the alkene 

• If the highest ranked substituents at each end are on the same face (cis), then it is a Z-alkene (Z-name) 

• If the highest ranked substituents at each end are on the opposite faces (trans), then it is an E-alkene (E-name) 

 

Z- or E- goes at the start of the name. If there is more than one alkene, put a number in front to denote which position the alkene starts at

Retinal stereoisomers 

• Double bonds cannot rotate 

• But in certain cases where high levels of conjugation (lots of double bonds in a row), can rotate between z- and e- forms 

• Eg rentinal stereoisomers change conformation/rotate in presence of light 

• Change in shape leads to impulse that causes vision 

Chirality 

Same connectivity, different three dimensional forms 

• Configurational isomers 

• Different spatial arrangements (configurations) around one or more carbon atoms 

• Most chiral molecules contain at least one chiral centre. 

• A carbon atom with FOUR DIFFERENT substituents attached is a chiral centre 

• A molecule with one or more chiral centres will usually exist as non-superimposable mirror image isomers (enantiomers) 

There are only two possible ways to arrange the substituents around a single chiral centre. 

The two are never superimposable = ENANTIOMERS 

enantiomers

Non-superimposable mirror image isomers are called enantiomers 

• A molecule with chiral centres has two enantiomeric forms in which the sense of chirality at the chiral centres is reversed 

• Enantiomers have identical atom connectivity and functional groups and differ only in the spatial orientation of the groups around a chiral centre 

• Enantiomers behave identically except in the presence of other chiral agents (chiral molecules; plane polarised light) 

 As biological molecules (e.g. proteins, nucleic acids) are chiral molecules, enantiomers often behave differently in the human body and other life forms 

Enantiomers and optical rotations 

Plane polarised light is a chiral environment (generated in a polarimeter) 

• A chiral molecule will make the light rotate either clockwise or anticlockwise: optical activity 

• A chiral molecule that rotates plane polarised light clockwise is dextrorotary (D), denoted (+) 

• its enantiomer rotates plane polarized light anticlockwise, is levorotatory (L), denoted (-)  

(From Latin dextra for right and laevus for left.) 

Racemic mixtures 

A 50:50 mix of enantiomers is called a “racemic mixture” or “racemate” 

Racemates can have different chemical properties from the individual enantiomers 

• Eg Racemates can have lower melting points, as pack less tightly compared to individual enantiomers

Naming stereoisomers: CIP rules 

Step 1: Rank the atom directly attached to each carbon of interest based on atomic number 

• Highest atomic number is highest priority (=1) 

• Lowest atomic number is lowest priority (=4) 

Step 2: If atoms are the same, look at their substituents and rank the next atoms out 

• Calculate based on the first point of difference 

 Step 3: If substituent contains double or triple bonds 

• Represent each multiple bond as single bond linkages to 2 or 3 different atoms of the same type 

• Ghost atoms are the 2nd and 3rd (for an alkyne) linkages and they are only attached  to the original partner; the real atom at the other end is treated as having a ghost version of the original partner 

Step 4: For a chiral centre, compare the relative spatial positions of the three highest ranked substituents in order, with the lowest priority substituent at the back 

• If the first to third highest ranked substituents are arranged in a clockwise manner, then the chiral centre is named R- 

• if the first to third highest ranked substituents are arranged in an anti-clockwise 

• manner, then the chiral centre is named S- 

enantiomer naming

1. Assign CIP priorities 

2. Make sure the lowest priority substituent is pointing “back” 

3. Ignoring the lowest priority substituent, determine direction 

4. R is clockwise number ordering, S is anti-clockwise 

Diastereoisomers 

• A molecule with more than one chiral centre has stereoisomeric forms in which the sense of chirality at some BUT NOT ALL OF the chiral centres is reversed: diastereoisomers (= diastereomers) 

• Diastereomers are not mirror image isomers 

• Diastereomers behave differently in the presence or absence of other chiral entities: they are different chemical entities 

• A molecule with two chiral centres usually has two enantiomeric forms (both chiral centres inverted), each of which has a diastereoisomeric form (four stereoisomers in total) 

Conformational isomers 

• Different 3D arrangements of atoms resulting from rotation around a single (σ) bond: conformational isomerism 

• Conformational isomers are also known as conformers 

• Interconversion is fast and continuous at normal temperatures 

• Can’t distinguish conformers based on bulk properties of the compound 

Protein conformation 

Protein conformation affect activity 

Kinase-ATP  

• conformations in cell  signalling 

Serotonin transporter  

• conformation for neural signalling 

Tau protein  

• conformation key to Alzheimer’s disease 

Reactivity

Why do reactions happen? What factors are important for reactivity? 

Bond stability (unstable/weak bond is more reactive) 

Electrons (valency and lone pairs) 

Bond motion (eg stretching, vibration)  -

• High energy means more stretch, breaks easily  

• Bond polarity 

Thermodynamics 

• Enthalpy (overall stability of all bonds in molecular entity compared between starting molecule and product) 

• Entropy (increased disorder, universe has tendency to move towards more disorder) 

• Changing conditions/environment 

Electronegativity 

measure of the ability of an atom in a molecule to attract electrons to itself 

• Increases across a row (lef to right) 

• Increases up a group (bottom to top) 

 Bonds between carbon-hydrogen are relatively unpolarised, share electrons evenly. Therefore, many organic molecules are based off them.  

bond polarity 

• A bond between two different elements with be polarised (since every element has different polarity) 

Ionic bonds: 

• Form between atoms with very different electronegativities (eg NaCl) 

Non-polar covalent bonds 

• Occur between identical atoms (H2) 

Polar covalent bonds 

• Occur between non-identical atoms with similar electronegativities (eg HF) 

In a polar covalent bonds, the more electronegative partner has a greater attraction for the bonding electrons 

• The electron density of the bond is greater closer to the more electronegative atom 

• δ+ means an atom has a partial positive charge on it 

• δ- means an atom has a partial negative charge on it 

• Dipole arrow shows the direction of electron polarisation (the cross is at the more positive end) 

Molecular dipoles 

Compounds with polarised bonds may or may not be polar, depending on symmetry (in a symmetrical molecule, bond polarities cancel out) 

Organic molecules with carbon chains and one (polar) functional group have a molecular dipole generally orientated towards the functional group

reaction mechanisms 

• A reaction mechanism shows a step-by-step picture of the way a reaction occurs 

• It breaks the reaction progress down into elementary steps 

A mechanism includes a description of: 

• how reactants interact 

• which bond(s) break(s) 

• which bond(s) form(s) 

• any intermediates formed 

• the order and timing of the steps 

Organic chemical reactions that occur in one step are concerted reactions (elementary reactions) 

• Concerted=all happens at same time 

Organic chemical reactions that occur in several steps are stepwise reactions (complex reactions) 

Studying reaction mechanism allow you to: 

• Predict the structure of products from new reactions 

• Understand/rationalise the outcome of a reaction 

• Predict the effect of changing the reaction conditions on the outcome of a reaction 

Reaction mechanisms are studied experimentally by kinetics and theoretically by computational methods 

Curly arrow 

• Curly arrows are a pictorial way to show mechanism in organic chemistry reactions 

• Chemists use curly arrows to show movement of electrons and, thus, bond formation and cleavage 

• In organic chemistry, used to show and work out mechanism of reaction 

full arrow head: motion of two electrons

hald arrow head: motion of one electron

base goes from nucleophile/lewis base (where electron comes from)

head goes to electrophile/lewis acid (where electrons go to)

nucleophile vs electrophile and heterolytic vs homolytic

Nucleophile=donate electron to form bond (base) 

Electrophile=receive electron to form bond (acid) 

Heterolytic: 2 electron movement

homolytic: 1 electron movement, creates radicals (not assessed)

curly arrow and heterolytic bond cleavage 

• Curly arrows show the motion of two electrons 

• Heterolytic cleavage is the breaking of a bond in an unsymmetrical fashion, leaving a negative charge at the atom that the electrons move to and a positive charge at the other end 

How to draw curly arrows: 

• In heterolytic cleavage the arrow goes from the bond (where the two electrons are) to the more electronegative atom 

• Orignally bond is sharing electrons, br takes electrons when seperating, causes C to be positive 

Curly arrow goes from bond towards more electronegative element 

curly arrow and Heterolytic bond formation 

• Heterolytic bond formation is the forming of a bond in an unsymmetrical fashion 

• The curly arrow points from an anion towards a cation OR from an electron rich centre towards an electron deficient one 

How to draw curly arrows: 

• In heterolytic bond formation, the curly arrow should point to where the new bond forms (which is where the electrons end up) 

• But sometimes it is clearer to have it pointing to the electrophile itself 

Curly arrows: heterolytic processes 

1. Drawing lone pair, then curly arrow from lone pair to hydroxide of acid, then another curly arro from bond to O  

2. Do same for second reaction 

Overall, draw curly arrow from broken bond to electronegative atom bonded to, then another curly arrow from reactant to now free atom that will bind 

curly arrows and resonance 

• Resonance is movement of electrons within a molecule or ionic system 

• Resonance is used when a single Lewis structure isn’t sufficient to show the bonding situation 

• Resonance is a stabilising effect (electron density and/or charge is spread over more area/atoms) 

• Resonance occurs through π-bonds and lone pairs 

Resonance stabilization of charged intermediates: 

Carboxylate: from lone pair towards double bond, then from double bond to electronegative atom 

benzylic cation: stabilisation of the cation by movement of positive charge due to defiency of electron spread over 7 atoms/carbons 

allylic cation: pi electrons donate e- to form resonance structures

Curly arrows and mechanism 

• A simple acid dissociation demonstrates the use of curly arrows in showing reaction mechanisms

• The mechanism of dissolution of hydrogen chloride (a strong acid) in water to form the hydroxonium ion can be shown using curly arrows: 

• Curly arrows are meant to show only electron motion, not molecular motion 

• We therefore draw the reactants ca. one bond length from each other 

lewis structure and mechanism 

• A reactant with a lone pair may donate it to form a new bond to an atom with a (partial) positive charge 

• Sharing electrons leads to a positive charge on the atom with the lone pair 

• The remaining lone pair on the product is not available for reaction because the positive charge deactivates it 

• When an electronegative atom or group cleaves from a neutral reactant (with the electrons of the bond), it becomes negatively charged 

• This is because it has gained an electron from the bond that it originally shared 

Classes of reactions: 

Substitution 

• Group substituted for another 

Addition 

• Group added 

Elimination 

• Group removed 

Redox 

• Acid/base 

why reactions and synthesis? 

Synthesis of complex molecules in order to: 

• Produce important and useful compounds (pharmaceuticals, agrochemicals, plastics, other materials, etc) 

• Confirm structure of naturally occurring molecules 

• Discover and develop new chemicals 

Complex molecules usually cannot be produced in a single step --> Reaction sequences! 

reaction sequences 

• Functional groups have certain reactivities 

• Based on their reactivity, functional groups react in certain ways and with specific reagent types 

• Therefore, in a complex synthesis, reactions have to be performed in the correct order to make the target molecule and to avoid competing and undesired reactions 

Eg synthesis of paracetamol 

• first reaction is substitution, second is reduction, third is substitution. Byproduct (isomer) of 1st substitution reaction must be removed via distillation to produce pure product 

Notation in reaction sequences 

• Reaction sequences can be abbreviated to show the overall transformation from starting material to final product 

• Reagents, catalysts and conditions are listed above/below the reaction arrow 

• The list of numbered steps should show each reaction in the sequence 

• Extra steps like work-up and purifications are often not shown in a multistep reaction sequence, or are within the same number as the reaction 

Eg synthesis of paracetamol can be abbreivated as: 

each number shows reaction order. Product of reaction 1 is reactant of reaction 2 and so on. Shows initial reactant and final product, with reagents above/below reaaction arrow numbered in order reaction occurs.  

• usually abbreviated reactions do not show purifications (eg distillation in paracetamol synthesis, or seperation in funnel aka work-up).  

reaction sequence problems 

• Research chemists try to work out how to make a certain target molecule starting from eadily available starting materials 

• They need to decide which reagents/catalysts to use and in which order to do the reactions 

• Some organic synthesis problems you may encounter are this type, i.e. given the starting material and product, work out the order of reactions as well as the reagents needed 

reaction sequence strategies

Strategy to solve a reaction sequence, given starting material and product: 

• Determine the key structural differences between the starting material and product 

• Try to map the carbon skeleton of the starting material onto that of the product 

• Work out whether new C-C bonds need to be formed 

• Work out if oxidations or reductions are required – could these have been part of the bond forming step or separate? (e.g. Grignard reaction) 

work out the structure of the product from a given reaction or reaction sequence

These are usually the easiest to solve, since you just work through each step sequentially: 

• The product of step 1 is the starting material for step 2 

• The product of step 2 is the starting material for step 3 

draw or name the starting material, given information about the product and reagents

• For this you need to work backwards from product: 

• Look at the product structure, particularly the carbon skeleton 

• Look at the reagents – do any of them introduce more carbons to the skeleton? These will be absent  from the starting material 

• What kind of functional group(s) does each reagent react with? Is the product of this type of reaction compatible with reagents in subsequent steps?

aryl halide

Aryl halide: halogen attached to benzene ring  

• Aryl halide require nucleophile (nitrogen/amine, and other aryl group and a catalyst (in this course is Pd) 

• Amine substation gives rise to aryl amine.  

• Aryl boronic ester substitution gives rise to aryl 

Bromomethane 

Broad-spectrum pesticide 

BUT... ozone depleting 

• Toxic to pests (and humans) 

• Carcinogenic (cancer causing) 

Methylates proteins 

• e.g. side chain of amino acids arginine or lysine or cystine 

• ➢ Protein methylation alters conformation and function 

Methylates DNA 

• e.g. guanine heteronuclear base 

• ➢ DNA methylation disrupts double helix structure, transcription and replication 

Generally, alkylating agents substitute at nucleophilic sites in biomolecules and can be harmful 

S-Adenosinosylmethionine (SAM) 

• A biological methylating agent 

• A coenzyme = a chemical reagent required for an enzymatic reaction 

• Methylates norepinephrine to produce adrenaline (increases blood pressure and heart rate) 

• SAM is itself formed by substitution reaction of the amino acid methionine with adenosine triphosphate (ATP) 

Synthesis of Tamiflu 

Influenza A and B drug 

Binds competitively to the viral neuraminidase enzyme 

• Prevents cleavage of cell-surface neuraminic (sialic) acid 

• Prevents new virus particles leaving the cell 

Substitution of a tosylate (TsO-) by azide ion (N3-) 

(Nucleophilic) Substitution Reactions 

• The starting material/electrophile (organic substrate) is a haloalkane, tosylate (biochem: phosphate or acetate) – compounds where an sp3 carbon is attached to a good LG. 

• leaving group is substituted by nucleophile 

• Nucleophile reacts at the carbon attached to the leaving group (which is now electrophilic) 

• The Nu and LG may be neutral (with a lone pair of electrons) or negatively charged (a salt form). 

• LG = Cl, Br, I, OTs, (bio: OPO3H, Oac) 

• Nu = ROH, RSH,R2NH, NaN3, NaCN, NaOR, NaSR, etc 

Structure of Organic Substrate 

• to react in an uncatalysed nucleophilic substitution reaction, the leaving group (I, Br, Cl, OTs, OPO3H, OAc) must be attached to the carbon framework at an sp3-hybridised centre 

• (Leaving group must be attached to tertiary carbon) 

Substitution reactions of primary vs. tertiary substrates 

Cannot work with charged nucleophile (NaOH), but with uncharged nucleophile (H2O). Reaction occurs via different mechanism 

NaOH works from primary but not for tertiary, Need H2O instead 

Reaction conditions reacting differently, mean must have different mechanisms 

SN2 mechanism= Substitution, Nucleophilic, Bimolecular 

Bond formation between nucleophilic and bond breakage between leaving group and carbon 

• Transition state: point of highest energy during the reaction - halfway between two points 

• Needs square brackets, double dagger, and dotted lines to represent bonds are partially formed 

 

• Primary and secondary organic substrates react by SN2 mechanism 

• Nucleophilic attack is fast due to low steric hindrance 

• A negatively charged Nu favours the SN2 mechanism 

• Nucleophilic attack is fast due to high electrostatic attraction between the Nu- and the electrophilic carbon of the organic substrate 

Sn2 Reaction Stereochemistry 

• Backside attack by Nu (180° from LG) leads to inversion of stereochemical configuration 

• Nu attacks from back as both electron rich, so repel. This is why it doesn't work for tertiary or sp2 hybridised substrates 

• Inversion is only detectable if the substitution occurs at a chiral centre, but the backside orientation of attack occurs in every SN2 substitution reaction 

SN1 Mechanism: Substitution, Nucleophilic, Unimolecular 

TS1=transition state 1, TS2=transition state 2 

Rate determining step almost always first step, as charged intermediates are almost always highest energy, therefore when transition, energy has increased the most (bond breakage is endothermic) 

Rate equation: rate is only dependent on conc of substrate, as first step is rate determining step (and only uses substrate, not nu) 

Tertiary organic substrates react by the SN1 mechanism 

• Nucleophile attack at the electrophilic C is slow due to high sterichindrance so this disfavours the SN2 mechanism (high energy TS) 

• A tertiary carbocation intermediate is highly stabilised so this favours the SN1 mechanism 

A neutral (uncharged) Nu favours the SN1 mechanism 

• Lower electrostatic attraction between the NuH and the electrophilic carbon of the organic substrate, SN2 attack is slower, so the intermediate has time to form 

SN1 Mechanism: Carbocation Stability 

For organic substrates (electrophiles) that can form stabilised carbocations, the SN1 mechanism is the preferred pathway for substitution 

can do inductive or resonance stabilisation

Inductive stabilisation 

R groups stabilise a carbocation by induction (donation of electron density) 

• the more carbon groups around, the more stabilised, as more bonds means more electrons capable of donating electron density) 

Resonance stabilisation 

• Conjugated π-bonds stabilise a carbocation by resonance 

Therefore, tertiary, benzylic and allylic substrates react efficiently by the SN1 mechanism

SN1 mechanism summary

• Two-step mechanism 

• Intermediate carbocation 

Each step has a TS: 

• TS1: partial bond C to LG 

• TS2: partial bond C to Nu 

Sn2 mechanism summary

• One-step mechanism 

• Concerted process 

• No intermediate 

SN1 Mechanism: Stereochemistry 

• Planar carbocation intermediate 

• Nucleophile can attack equally from either side 

• Racemic mixture results if at a chiral centre 

Substitution Reactions of Alcohols 

For substitution of alcohols, the hydroxy group (OH) needs to be converted to a good leaving group 

1. Use a Bronsted acid to protonate OH (make it water) then substitution with the conjugate base of the Bronsted acid (one reaction with multiple mechanistic steps) easily occurs 

Enzymes catalyse substitution reactions of alcohols by protonation 

2. An alcohol can be converted into a good leaving group such as halide, tosylate, acetate or phosphate, then a subsequent substitution reaction occurs (two reactions) 

Elimination Reactions 

The starting material (organic substrate) is a haloalkane, tosylate (bio: phosphate or acetate), with a proton attached to the adjacent carbon to the LG = Lewis acid. 

• Proton attached to next door carbon as leaving not, not same carbon 

• Carbon to leaving group bond breaks, H and C bond breaksbond between proton and leaving group carbons break and form pi bond 

The Base and LG may be neutral (with a lone pair of electrons) or negatively charged (present as a salt) 

• LG = Cl, Br, I, Ots (bio: OPO3H, Oac) 

• Base = tBuOH, R3N,  NaOH, NaOR, NaNH2, NaH, etc 

elimination Example- Fosinopril 

• Inhibitor of angiotensin converting enzyme 

• Drug for treating high blood pressure 

• The synthesis of the right-hand side of this drug includes an elimination of H-OH (water, shown in a slightly different way) 

Elimination reaction mechanism  types

• Two mechanistic extremes for elimination: 

• ➢ E1 mechanisms (unimolecular elimination) 

• ➢ E2 mechanisms (bimolecular elimination) 

E2 Reaction Mechanism: Elimination, Bimolecular 

• Rate=k[substrate] [base] 

Reactive conformation: antiperiplanar H, LG (180° dihedral angle) 

• Leaving group and H need 180 dihedral angle to bond base 

• Has transisiton state 

Reaction Energy Diagram for E2 

• One-step mechanism 

• Concerted process 

• No intermediate 

• Transition state: partial bonds to LG, H, base and partial π bond 

E2 Mechanism: Stereochemistry 

• If both the E- and Z-alkenes can form, the E-alkene will be the major product 

• Steric factors disfavour the largest substituents being close (higher energy transition state) 

• In compounds with only one H that can eliminate, the stereochemistry of the alkene is dependent on the configuration of the starting material 

E2 Mechanism: Regioselectivity 

• Usually, the more substituted alkene will be formed preferentially in a reaction, if it is mechanistically possible 

• alkenes with a more substituted double bond are more stable (lower energy) than isomers with a less substituted double bond = Zaitsev’s rule 

zaitsefs rule

• alkenes with a more substituted double bond are more stable (lower energy) than isomers with a less substituted double bond

An exception to the usual Zaitsev selectivity occurs with a very bulky base, e.g. tert-butoxide 

• tert-butoxide is sterically bulky, so elimination of the more hindered proton (to give the more substituted alkene) is very slow, so formation of the less substituted alkene is the faster process 

E1 Reaction Mechanism: Elimination, Unimolecular 

• Step 1: rate determining, LG leaves, forms transition state 1, then carbocation intermediate 

• Step 2: base joins, forms transition state 2 then producr + [base-H]+ 

• Rate=k[substrate] 

Reaction Energy Diagram for an E1 Reaction 

• Two-step mechanism 

• Stepwise process 

• Forms carbocation intermediate 

• First step is rate determining 

E1 Mechanism: Stereochemistry 

The E-alkene is the major product because it is more stable than the corresponding Z-alkene, and therefore the transition state leading to it is lower in energy (so formation of the E-alkene is the faster process) 

E1 Mechanism: Regioselectivity 

Usually, the more substituted alkene will be formed preferentially in a reaction, if it is mechanistically possible  

• alkenes with a more substituted double bond are more stable (lower energy) than isomers with a less substituted double bond = Zaitsev’s rule 

Elimination Reactions of Alcohols 

Dehydration 

• Use an acid with a non-nucleophilic counterion (conjugate base), ideally concentrated H2SO4 

• Use an acid with a non-nucleophilic counterion (conjugate base) to avoid a competing substitution reaction, ideally concentrated H2SO4 

 regioselectivity:

selectivity in the region where reactant bonds to alkene

markovnikovs rule

Markovnikov’s Rule: “In additions of a hydrogen halide to an unsymmetrical alkene, the hydrogen adds to the end of the double bond with the most hydrogens, and the halogen adds to the C with fewer hydrogens.”

• Markovnikov: rich get richer, hydrogen added to Carbon already with most hydrogen makes major product

• Anti-markovnikov=minor product, hydrogen added to carbon with least hydrogen already

mechanism of markovnikovs rule: due to carbocation stability

Additions to pi-systems 

The most common chemical transformation of a carbon-carbon double bond is the addition reaction 

• pi bond is broken, A-B groups added to carbons that were involved in alkene 

Qinghaosu  - Alkene addition reactions - example 

• active ingredient of the traditional Chinese herbal medicine Artemisia annua L. 

• synthesised by the pharmaceutical company Hoffmann-La Roche in 1983; the synthesis included this alkene addition reaction 

Steroids  - Alkene addition reactions - example 

• The biosynthesis of steroids involves a series of alkene addition reactions 

• The first reaction is epoxide formation by addition of flavin hydroperoxide to an alkene functional group in squalene

Bonding in alkenes 

Alkenes are nucleophiles 

• Single bond = only sigma bond 

• Double bond = sigma bond plus pi bond 

• Double bonds are stronger than single bonds 

• Double bonds can’t rotate 

• sigma bonds are stronger than pi bonds 

Mechanism of addition of HX to alkenes 

• C=C pi bond breaks + H-X bond breaks --> C-X bond forms + C-H bond forms 

• H is electrophli, wants to grab electrons. 

• Curly arrow goes from source of electrons towards electrophilic atom 

• carbocation intermeditae lost electrons making up pi bond, becomes positivly charged 

• X- has high electrostatic attraction, so reacts very quickly with Carbon, forms final product 

 

• can almost always expect first step to be rate determining step, as intermediate almost always higher energy 

• Forms carbocatoin intermediate 

• Addition reactions are always stepwise, bi-molecular (no unimolecular evivelent) 

Addition of HX to alkenes; stepwise or concerted? 

• For references, sn2 is concerted, sn1 is stepwise   

This reaction has 2 bond breakgaes, and formations, but cannot tell only from this is concerted or stepwise.   

• However, chemists cans tudy reactant and product to see that reaction passes through an intermediate, making it stepwise (no intermediate in a concerted reaction) 

Mechanistic attack of addition reactions 

• mechanistically doesn't matter if Br comes from bottom or top face 

• Other bonds are identical (not chiral centre), therefore attack from either side doesn't have any affect on final product (equal geometry)  

Regioselectivitiy in H-X addition 

• Markovnikov’s Rule: “In additions of a hydrogen halide to an unsymmetrical alkene, the hydrogen adds to the end of the double bond with the most hydrogens, and the halogen adds to the C with fewer hydrogens.” 

• Markovnikov: rich get richer, hydrogen added to Carbon already with most hydrogen makes major product 

• Anti-markovnikov=minor product, hydrogen added to carbon with least hydrogen already 

Carbocation stabilisation and markovnikov/regioselectivity 

• carbon with + charge has 3 R groups on it (tertairy carbon), so can donated electron density to carbocationic charge in the bonds, stabilising them (carbocation stabilisation). 

• Therefore intermediate is reasonably well stablised 

 

• Carbon wih + charge has only 1 R group on it (primary carbon), Hydrogens cannot donate electron density (only electrons in H are in bond), therefore cannot stabilised by electron density sharing alone, tehrefore much slower pathway as passes through very high energy intermediate (disfavoured) 

• Therefore major product is favoured as intermedite is lower energy, so easier to do, so happens more often 

Primary/tertairy carbocation stability 

The stability of a carbocation intermediate depends on the number and type of substituents: 

• Inductive stabilisation by attached alkyl groups 

• Resonance stabilisation by attached π-system 

tertairy more stablised than secondary more stablised than primary for inductive stabilisation 

Primary carbocations have much lower stabilisation, therefore form slower by a much higehr energy process 

• benzylic and allylic resonance structrues are well stabilised by sharing of electrons 

Energy profile diagram for an addition reaction: Unsymmetrical alkene 

• transition state for primary carbocation is at higher energy (less stable) 

• Transition state for secondary carbocation is at lower energy (more stable) 

• A more stable carbocation is formed  faster and provides the major product. 

Mechanism of addition of H2O to alkenes 

C=C pi bond breaks + H-OH bond breaks --> C-O bond forms + C-H bond forms 

• H2O is a much weaker acid than HCl, HBr and HI 

The uncatalysed addition reaction of water with an alkene is very slow 

• Use a Bronsted acid catalyst (e.g. dilute H2SO4) 

water removes H+ from OH group on product to make a neutral oxygen.   

This final step regenerates the reagenet.   

• Therefore reagent is dil.sulfuric acid, but only h20 is used, the extra proton is used as a catalyst, therefore reagent can be regenerated. 

Carbonyl compounds

molecule containing c group to O double bond 

Different X group change what type it is 

• OH: carboxylic acid 

• OR= ester 

• Cl=acid chloride 

• NH2/NHR/NR2= amises 

• R(alkyl)=ketone 

• H=aldehydes 

Reactivity of the carbonyl group 

as sigma and pi bonds making up double bond 

• pi bond e- higher energy than sigma bond e-, therefore always pi electrons involved in reaction 

•  2 electron in sigmoa bond and 2 in pi bond,  

• 4 electron in 2 n-orbitals (n-nonbonding) 

C=O double bond is different from C-C bond 

C=O bond is polarised, because O has higher electronegativity, therefore e- are slighty closer to O 

• Therefore C centre is electrophilic, susceptible to attack by nucleophiles 

Carbonyl compounds examples 

• Damasceone: scent of roses 

• Amoxycilin: a penicilin antibiotic 

• Dacron=terylene: a polyester used in clothing 

• Testosterone: male sex hormone 

Reaction Types – Redox reactions 

Oxidation 

• Increase in number of C-O bonds 

• and/or 

• Decrease in number of C-H bonds 

Reduction 

• Decrease in number of C-O bonds 

• and/or 

• Increase in number of C-H bonds 

OILRIG: oxidation is loss, reduction is gain 

• Particularly useful for metal centres

Oxidation Involving Carbonyls 

• Increase in number of C-O bonds 

• Decrease in number of C-H bonds 

 

• reactant has 1 C-O bond, intermediate has 2 C-O bond, and product has 3 C-O bond. 

• Overall increase in C-O bonds and decrease in C-H bonds 

• because happens in water, reaction cannot be stopped at aldehyde and continues to carboxylic acid 

Primary alcohol --> aldehyde: oxidation

• PCC is selective oxidant that oxidises primary alcohol to aldehyde that doesn't progress to carboxylic acid, as used in organic solvent, nto water 

• if secondary alcohol, can use any of normal oxidants to make ketone. Cannot be further oxidised to carboxylic acid as not further C-H groups of oxidate 

• If tertariy alcohol, nothing happens, as no C-H at alcohol carbon to oxidise 

Reduction Involving Carbonyls 

• Decrease in number of C-O bonds 

• Increase in number of C-H bonds 

 

• oxidoreductase is enzyme used in biological reactions that needed catalyst of NADH/NADPH to work 

• Aldehyde to primary alcohol: lose 1 C-O bond and gain C-H bond 

• Ketone to secondary alcohol: lose 1 C-O bond, Gain C-H bond 

• reductants 

• NaBH4 (mild) 

• LiAlH4 (strong)