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Revision Notes, Chemistry 2, complete

Chemistry 2 (University of Melbourne)

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2.7 Acids and Bases: The BrØnsted-Lowry Definition

9 Acidity and bacidity are related to a molecules electronegativity and polarity.
9 Acids donate protons, and bases accept protons
9 Water can act either as an acid or a base

2.8 Acid and Base Strength

9 Acids differ in their ability to donate protons, some reacting almost completely and others
only slightly. The strength is indicated by the acidity constant, which resembles the degree
to which an acid is ionised in solution.
9 Stronger acids have their equilibria more towards the right and have larger acidity constants.
9 pKa=-logKa
9 A stronger acid has a smaller pKA and a weaker acid has a larger pKa.
9 There is an inverse relationship between the acid strength of an acid and base strength of its
conjugate base.

2.9 Predicting Acid-Base Reactions from pKa Values

9 An acid will donate a proton to the conjugate base of a weaker acid, and the conjugate base
of a weaker acid will remove the proton from a stronger acid.
9 The product conjugate acid in an acid-base reaction must be weaker and less reactive than
the starting base.

2.10 Organic Acids and Organic Bases

9 Organic acids are characterized by the presence of a positively polarized hydrogen atom, and
are of two main kinds:
(1) Contain a hydrogen tom bonded to an electronegative oxygen atom (i.e.
methanol and acetic acid)
(2) Contain a hydrogen atom bonded to a carbon atom next to a C=O bond (i.e.
acetone)
9 In both cases acidity is due to the fact that the conjugate base resulting from loss of proton
is stabilized by having its negative charge on a strongly electronegative oxygen atom. It is
additionally stabilized by resonance.
9 The acidity of ketones is due to the conjugate base resulting from loss of a proton is
stabilised by resonance. Additionally one of the resonance forms stabilises the negative
charge by placing it on an electronegative oxygen atom.
9 Organic bases are characterized by the presence of an atom with a lone pair of electrons
that can bond to protons. Nitrogen containing compounds are most common, followed by
oxygen containing compounds.

5.2 How Organic Reaction Occur: Mechanisms

9 A reaction mechanism is an overall description of how a reaction occurs- i.e. exactly what
takes place at each stage of a chemical transformation.
9 Considers which bonds are broken an in what order.
9 A bond can break in an electronically symmetrical way so that one electron remains with
each product fragment. This is called homolytic.

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9 A bond can also break in an electronically unsymmetrical way so that both bonding electrons
remain with one product fragment, leaving the other with a vacant orbital. This is called
heterolytic.
9 A bond can form in an electronically symmetrical way if one electron is donated to the new
bond by each reactant or in an unsymmetrical way if both bonding electrons are donated by
one reactant.
9 Radical (neutral chemical species that contains an odd number of electrons and has single
unpaired electron) reactions involve symmetrical bond-breaking and bond-making.
9 Polar reactions involve unsymmetrical bond-breaking and bond-making and are the most
common reaction.

5.4 Polar Reactions

9 Polar reactions occur because of the electrical attraction between positive and negative
centres on functional groups in molecules.
9 Most organic compounds are electrically neutral, they have no net charge.
9 Bond polarity is a consequence of an unsymmetrical electron distribution in a bond and is
due to the difference in electronegativity of the bonded atoms.
9 Metals are less electronegative than carbons.
9 As the electric field around a given atom changes because of changing interactions with
solvent or other polar molecules nearby, the electron distribution around that atom also
changes. The measure of this response to an external electrical influence is called the
Polarizability of the atom.
9 Large atoms with more, loosely held electrons are more polarisable, and smaller atoms less
so.
9 The fundamental characteristic of all polar organic reactions is that electron rich sites react
with electron poor sites.
9 A nucleophile is a substance that is “nucleus-loving”, has a negatively polarized, electron-rich
atom and can form a bond by donating a pair of electrons to a positively charged; ammonia,
water, hydroxide ion.
9 An electrophile has a positively polarized, electron poor atom and can form a bond by
accepting a pair of electrons from a nucleophile.

5.6 Using Curved Arrows in Polar Reaction Mechanisms

9 An electron pair moves from the atom at the tail of the arrow to the atom at the head of the
arrow.
9 Rules of arrows:
(1) Electrons move from a nucleophilic (Nu: or Nu:-) source to an electrophilic sink
(E or E+)
(2) The nucleophile can be either negatively charged or neutral
(3) The electrophile can be either positively charged or neutral
(4) The octet rule must be followed.

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6.8 Orientation of Electrophilic Additions: Markovnikov’s Rule

9 Reactions in which an unsymmetrical substituted alkene has given a single addition product
are regiospecific, when only one of the two possible orientations occur.
9 In the addition of HX to an alkene, the H attaches to the carbon with fewer alkyl substituents
and the X attaches to the carbon with more alkyl substituents.

6.9 Carbocation Structure and Stability

9 Carbocations are planar, with the pi orbital being unoccupied.
9 The stability of carbocations increases with increasing substitution so that the stability order
is tertiary > secondary > primary > methyl.
9 To determine carbocation stabilities one may measure the energy required to form the
carbocation by dissociated of the corresponding alkyl halide.
9 Inductive effects result from the shifting of electrons in a sigma bond in response to the
electronegativity of nearby atoms, thus the more alkyl groups there are attached to the
positively charged carbon, the more electron density shifts toward the charge and the more
inductive stabilisation of the cation occurs.
9 Hyperconjugation is the stabilising interaction between a vacant p orbital and properly
oriented C-H bonds on neighbouring carbons.

6.10 The Hammond Postulate

9 Electrophilic addition to an unsymmetrically substituted alkene gives the more highly
substituted carbocation intermediate.
9 A more highly substituted carbocation is more stable than a less highly substituted one.
9 The more stable intermediate is forms faster than the less stable one.
9 Transition states are high-energy activated complexes that occur transiently during the
course of a reaction and represent an energy maximum.
9 Hammond Postulate: The structure of a transition state resembles the structure of the
nearest stable species. Transition states for endergonic steps structurally resemble products,
and transition states for exergonic steps structurally resemble reactants.
9 The transition state for alkene protonation structurally resembles the carbocation
intermediate
9 The transition state is stabilised by hyperconjugation and inductive effects in the same way
as the product carbocation.

7.4 Addition of Water to Alkenes: Oxymercuration

9 Water adds to alkenes to yield alcohols, in the presence of a strong acid catalyst (HA).
9 Results in a carbon intermediate which reacts with water to yield a protonated alcohol
product.
9 Biological hydration requires that the double bond be adjacent to a carbonyl group for
reaction to proceed.
9 Alkenes are often hydrated by Oxymercuration
9 Nucleophilic addition of water as in halohydrin formation, followed by loss of a proton, then
yields a stable organo-mercury product.

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7.7 Reduction of Alkenes: Hydrogenation

9 In the presence of a metal catalyst alkenes react with H2- the hydrogen bond has been
hydrogenated or reduced.
9 In organic chemistry a reduction is a reaction that results in a gain of electron density by
carbon, caused either by bond formation between carbon and a less electronegative atom or
by bond-breaking between carbon and a more electronegative atom.
9 Catalytic hydrogenation is a heterogenic process rather than a homogenous one- takes place
on the surface of insoluble catalyst particles.
9 Molecular hydrogen and the alkene adsorb to catalyst surface and dissociate, a hydrogen ion
is transferred between them forming an artificially reduced intermediate with a C-H bond. A
second hydrogen is transferred from the metal to the second carbon, giving the alkane
product and regenerating the catalyst.
9 Aldehydes, ketones, esters and nitriles survive normal alkene hydrogenation conditions
unchanged, although reaction with these groups does occur under more vigorous
conditions.

11.1 The Discovery of Nucleophilic Substitution Reactions

9 Nucleophilic substitution reactions involve the substitution of one nucleophile or hydroxide
ion with another. R-X + Nu:- Æ R-Nu + X:-
9 The inversion of stereo chemical configuration must therefore take place in the second step,
the nucleophilic substitution of tosylate ion by acetate ion.
9 The nucleophilic substitution reaction of a primary or secondary alkyl halide or tosylate
always proceeds with inversion of configuration.

11.2 The SN2 Reaction

9 There is a direct relationship between the rate at which the reaction occurs and the
concentrations of the reactants. Measuring this is an indication of the kinetics of the
reaction.
9 Substitutions occurs at different rates depending upon temperature, concentrations and pH.
9 Second order reaction: reaction rate is linearly dependent on the concentrations of two
species.
9 Reaction rate = rate of disappearance of reactant
= k X [RX] X [OH-]
9 SN2 short for, substitution, nucleophilic and bimolecular.
9 Takes place in a single step without intermediates when the incoming nucleophile reacts
with the alkyl halide or tosylate (the substrate) from a direction opposite the group that is
displaced (the leaving group)
9 Nucleophile must approach from the opposite end of the molecule to the leaving group.
9 Stereo chemical configuration is reversed compared the original molecule.

11.3 Characteristics of the SN2 Reaction

9 The rate of a chemical reaction is determined by the energy difference between reactant
ground state and transition state.
9 The transition state for reaction of a sterically hindered (i.e. 3 methyl groups) alkyl halide,
whose carbon atom is shielded from approach of the incoming nucleophile is higher in

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energy and forms more slowly than the corresponding transition state for a less hindered
alkyl halide.
9 Nucleophile attacks carbon from the back
9 SN2 reactions occur only at relatively unhindered sites, usually only primary and a few
secondary halides.
9 The exact nucleophilicity of a species in a given reaction depends on the substrate, the
solvent, and even the reaction conditions.
9 Nucleophilicity roughly parallels basicity: strong bases often make strong nucleophiles.
9 Nucleophilicity usually increases going down a column of the periodic table as larger atoms
hold their valence electrons less tightly are and consequentially more likely to react.
9 Negatively charged nucleophiles are usually more reactive than neutral ones (reactions
generally carried out under basic conditions)
9 As the leaving group is expelled with a negative charge the best leaving groups are those
that best stabilize the negative charge in the transition state; i.e. Cl-.
9 An alcohol can be treated with para-toluenesulfonyl chloride to form a tosylate to improve
its reactivity towards nucleophilic substitution.
9 Protic solvents (containing an –OH or –NH group) are generally the worst for SN2 as they
undergo salvation of the reactant nucleophile and polar aprotic solvents (polar but neither
of above groups) are the best as they raise the ground state energy of the nucleophile.
9 Substrate characteristics: methyl and primary substrates.
9 Nucleophile: basic, negatively charged with a higher ground state energy.
9 Leaving group: more stable anions.
9 Polar aprotic solvents which surround the accompanying cation.

11.4 The SN1 Reaction

9 Tertiary halide substrates are most effective in SN1 reactions, and is the only factor upon
which the reaction rate is dependent.
9 Unimolecular rate limiting step. Reaction takes place by loss of the leaving group before the
nucleophile approaches.
9 Reaction occurs through a carbocation intermediate, with products showing a 1:1 ratio of
stereo chemical isomers of original asymmetric molecule.

11.5 Characteristics of the SN1 Reaction

9 Reaction is favoured whenever a stable carbocation is formed. As a result of resonance
stabilization, tertiary carbocations are the most stable and thereby the most likely to react.
9 Most stable leaving groups are more reactive, i.e. tertiary alcohols.
9 Nucleophiles do not affect the rate of SN1 reactions.
9 Solvent effects in SN1 reaction are due largely to stabilization or destabilization of the
transition state. Takes place more rapidly in strongly polar solvents, such as water and
methanol.
9 SN1 reactions are favoured in protic solvents because the transition-state energy leading to
carbocation intermediate is lowered by salvation.

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11.7 Elimination Reactions of Alkyl Halides: Zaitsev’s Rule

9 Elimination reactions are more complex due to the issues of regiochemistry and what
products are expected to result.
9 Zaitsev’s rule: in the elimination of HX from an alkyl halide, the more highly substituted
alkene product predominates.
9 Can be carried out through different mechanisms, E1 or E2.

11.8 The E2 Reaction and the Deuterium Isotope Effect

9 Occurs when an alkyl halide is treated with a strong base, such as hydroxide ion or alkoxide
ion (RO-)
9 Takes place in one step including high energy transition state
9 Both base and alkyl halide determine the reaction rate.
9 Deuterium isotope effect: C-H breaks more quickly than C-D.
9 Syn periplanar (requires the substituents be eclipsed) and anti periplaner (preferred because
it allows the substituents on the two carbons to adopt a staggered relationship) geometry
are possible

11.10 The E1 and E1cB Reactions

9 The dissociation of the alkyl halide with the carbocation is the slow rate-limiting step.
9 Occur in a Protic solvent with a non-basic nucleophile.
9 There is no geometric requirement on the E1 reaction because the halide and the hydrogen
are lost in separate steps.
9 E1cB reaction; takes place through a carbanion intermediate, base-induced abstraction of a
proton in a slow, rate-limiting step gives an anion, which expels a leaving group on the
adjacent carbon.

11.12 A Summary of Reactivity: SN1, SN2, E1, E1cB and E2

9 Primary alkyl halides: Sn2 substitutions occurs if a good nucleophile is used, E2 limination
occurs if a strong base is used, and E1cB elimination occurs if the leaving group is two
carbons away from a carbonyl group.
9 Secondary alkyl halides: Sn2 substitution occurs if a weakly basic nucleophile is used in a
polar aprotic solvent, E2 elimination predominates if a strong base is used, and E1cB
elimination takes place if the leaving group is two carbons away from a carbonyl group.
Secondary allylic and benzylic alkyl halides can also undergo Sn1 and E1 reactions if a weakly
basic nucleophile is used in a Protic solvent.
9 Tertiary alkyl halides; E2 elimination occurs when a base is used, but Sn1 substitution and
E1 elimination occur together under neutral conditions, such as in pure ethanol or water.
E1cB elimination takes place if the leaving group is two carbons away from a carbonyl group.

16.1 Electrophilic Aromatic Substitution Reactions: Bromination

9 When a reagent approaches an alkene, the electrophilic hydrogen is attracted to the p
orbitals of the double bond and forms a bond to one carbon, leaving a positive charge at the
other carbon. This intermediate then reacts with the nucleophile to yield the addition
product.

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9 Aromatic rings are less reactive towards electrophiles than alkenes are, although they are
more stable due to resonance.
9 The reaction of an electrophile with a benzene ring is endergonic, has a substantial
activation energy, and is rather slow.
9 The carbocation intermediate loses H+ from the halide bearing carbon to give a substitution
product.

16.2 Other Aromatic Substitutions

9 Chlorine and iodine can be introduced into aromatic rings by electrophilic substitution
reactions, but fluorine is too reactive and has a poor yield.
9 Aromatic rings react with Cl2 in the presence of FeCl3.
9 Iodine is only reactive towards aromatic rings in the presence of a copper salt or hydrogen
peroxide.
9 Aromatic rings can be nitrated by reaction with a mixture of concentrated nitric and
sulphuric acids with the electrophile being NO2+ which is generated from HNO3 by
protonation and loss of water. Forms nitrobenzene.
9 Aromatic rings can be sulfonated by reaction with fuming sulphuric acid, a mixture of H2SO4
and SO3. The electrophile is either HSO3+ or neutral SO3. Favoured in strong acid, but
desulfonation in hot dilute aqueous acid.
9 Hydroxylation of an aromatic ring to yield a hydroxybenzene occurs more frequently in
biological processes and is difficult to synthesize in a laboratory.

16.3 Alkylation and Acylation of Aromatic Rings: The Friedel-Crafts Reaction

9 Alkylation is the introduction of an alkyl group onto the benzene ring; by treating the
aromatic compound with an alkyl chloride RCl in the presence of AlCl3 to generated a carbon
electrophile R+.
1. Only alkyl halides can be used
2. Not on aromatic rings that are substituted by a strongly electron-withdrawing group
such s carbonyl or an amino group.
3. Difficult to stop the reaction after a single substitution.
4. Skeletal rearrangement of the alkyl carbocation electrophile sometimes occurs.
9 An aromatic ring can be acylated by reaction with a carboxylic acid chloride RCOCl in the
presence of AlCl3 (same limitations apply as above)

16.4 Substituent Effects in Substituted Aromatic Rings

9 Substituents affect the reactivity of the aromatic ring, some activating or deactivating it. i.e.
in nitration –OH activates and –NO2 deactivates.
9 Substituents affect the orientation of the reaction ; ortho and para directing activators,
ortha and para directing deactivators and meta directing deactivators.
9 An inductive effect is the withdrawal or donation of electrons through sigma bond due to
electronegativity; e.g. halogens, hydroxyl groups, carbonyl groups, cyano groups and nitro
groups.
9 Alkyl groups inductively donate electrons.
9 A resonance effect is the withdrawal or donation of electrons through a pi bond due to the
overlap of a p orbital on the substituent with a p orbital on the aromatic group

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9 Halogen, hydroxyl, alkoxyl and amino substituents donate electrons to the aromatic ring by
resonance. Lone pair electrons flow through, placing a negative charge in the ring.

16.5 An Explanation of Substituent Effects

9 Activating groups donate electrons to the ring and stabilize the carbocation intermediate
and lowering the activation energy for its formation. E.g. hydroxyl and amino groups.
9 Deactivating groups withdraw electrons from the ring making it more electron poor and
thereby destabilizing the carbocation intermediate, raising the activation energy for its
formation. E.g. carbonyl, cyano and nitro groups.
9 Inductive and resonance effects account for the directing effects of substituents as well as
for their activating or deactivating effects.
9 Ortho and para intermediates are more stabilized than the meta intermediate. Only ortha
and para have resonance forms in which the positive charge is stabilized by donation of an
electron pair form oxygen.
9 Hydroxyl, alkoxyl and amino groups are also ortha-para activators, but for a different reason
than for alkyl groups.
9 Halogens are deactivating because their stronger electron withdrawing inductive effect
outweighs their weaker electron donating resonance effect. Have a stronger electron
withdrawing inductive effect but a weaker electron-donating resonance effect and are thus
deactivators.

16.9 Oxidation of Aromatic Compounds

9 The benzene ring is inert to strong oxidising agents such as KMnO4 and Na2Cr2O7, however
alkyl side chains react rapidly with oxidising agents and are converted into carbonyl groups,
converting alkylbenzene into a benzoic acid.
9 Side chain bromination at the benzylic position occurs when an alkylbenzene is treated with
N-bromosuccinimide. Bromination occurs exclusively in the benzylic position and does not
give a mixture of products.

17.7 Naming Alcohols and Phenols

9 Alcohols oxidise to yield carbonyl compounds. Primary alcohols Æ aldehydes or carboxylic
acids, secondary alcohols Æ ketones, tertiary alcohols Æ do not normally react.
9 Reagent s including KMnO4, CrO3 and Na2Cr2O7 may be used depending on availability and
cost.

19.4 Nucleophilic Addition Reactions of Aldehydes and Ketones

9 The most general reaction of aldehydes and ketones is the nucleophilic addition reaction. A
nucleophile approaches along the C=O bond and adds to the electrophilic C=O carbon atom.
Instantaneously rehybridisation of the carbonyl carbon from sp2 to sp3 occurs and an
electron pair moves to the oxygen, giving it a negative charge. This is then reacted with an
acid to form an alcohol.
9 Aldehydes are generally more reactive than ketones in nucleophilic addition reactions
because of the greater polarization of aldehydes carbonyl groups.
9 A primary carbocation is higher in energy and more reactive than a secondary carbocation.

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9 Aromatic aldehydes are less reactive in nucleophilic addition reactions than aliphatic
aldehydes because the electron donating resonance effect of the aromatic ring makes the
carbonyl group less electrophilic.

19.6 Nucleophilic Addition of HCN: Cyanohydrin Formation

9 Aldehydes and unhindered ketones react with HCN to yield cyanohydrins. Occurs slowly
when pure HCN is used but rapidly when a small amount of base is added to generate the
nucleophilic cyanide ion CN-.
9 Cyanohydrin formation is useful as further chemistry can be carried out on the product- can
be reduced be hydrolysed by hot aqueous acid to yield a carboxylic acid.

19.7 Nucleophilic Addition of Grignard and Hydride Reagents: Alcohol Formation

9 Aldehyde or ketone + Grignard reagent RMgX Æ alcohol
9 Grignard reaction; Mg2+ adds to the carbonyl oxygen atom of the aldehyde or ketone
making the carbonyl group a better electrophile. R:- then adds through nucleophilic addition
then produces a tetrahedral magnesium alkoxide intermediate, and protonation by addition
of water or dilute aqueous acid in separate steps.
9 Grignard additions are effectively irreversible as the carbanion is too poor a leaving group.
9 Addition of water or aqueous acid after the hydride addition step protonates the
tetrahedral alkoxide intermediate and gives the alcohol product.

19.8 Nucleophilic Addition of Amines: Imine and Enamine Formation

9 Primary amines RNH2 + aldehyde or ketone Æ imine R2C=NR. These are common in
biological pathways. Leads to a C=N bond. Reversible, acid-catalysed process.
9 Nucleophilic addition of the primary amine to the carbonyl group, followed by transfer of a
proton from nitrogen to oxygen to yield a neutral amino alcohol.
9 Secondary amines R2NH Æ enamine R2N-CR=CR2. Leads to a C=C bond. No proton on
nitrogen that can be lost to form a neutral imine product, instead a proton is lost from the
neighbouring carbon yielding enamine.
9 Maximum rates at weakly acidic pH or 4-5.

21.3Nuclephilic Acyl Substitution Reactions of Carboxylic Acids

9 Under circumstances acid chlorides, anhydrides, esters and amides can all be prepared from
carboxylic acids.
9 Carboxylic acids Æ acid chlorides by treatment with SOCl2 forming HCl and SO2
9 Acid anhydrides; acetic acid at temperature of 800 degrees
9 Carboxlic acid + CH3X Æ eter
9 Fischer esterification reaction; reactivity enhanced by HCl or H2SO4. Mineral acid protonates
the carbonyl-group oxygenation, thereby giving the carboxylic acid a positive charge and
rendering it much more reactive, followed by loss of water.
9 In amide formation the OH must be replaced by a better, nonacidic leaving group. E.g.
treated with DCC to activate it, followed by addition of the amine.
9 Reduction is a nucleophilic acyl substitution in which –H replaces –OH to give an aldehyde,
which is further reduced to a primary alcohol by nucleophilic addition.

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9 The hydride ion is a base as well as a nucleophile allowing the nucleophilic acyl substitution
to take place on the carboxylate ion rather than on the free carboxylic aid and gives a high-
energy dianion intermediate.
9 Borane reacts with carboxylic aids faster than with any other functional group
9 In the laboratory the acid must first be activated, often achieved by reaction with ATP in
living organisms.

21.4 Chemistry of Acid Halides

9 Acid chlorides are prepared from carboxylic acids by reaction with thionyl chloride SOCl2
9 Carboxylic acid + PBr3 + ether Æ acid bromide
9 Halogens in aid halides can be replaced by –OH or –OCOR or –OR or –NH2.
9 Acid chlorides react with water to yield carboxylic acids in a hydrolysis reaction, HCl is a by-
product. Carried out under NaOH catalyst to remove HCl
9 Acid chloride + carboxylate anion Æ acid anhydride.
9 Acid chloride + alcohol Æ ester. Carried out under NaOH catalyst. Reaction is affected by
Steric hindrance primary > secondary > tertiary alcohols produced.
9 Acid chloride + ammonia Æ amines and amides. 2 equivalents of amine must be used.
9 Acid chloride + LiAlH4 Æ aldehyde Æ primary alcohols
9 Grignard reagents react with acid chlorides to yield tertiary alcohols in which two of the
substituents are the same. A KETON INTERMEDIATE IS AMDE.

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