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Organic Chemistry

Organic Reactions

Reaction Mechanisms A reaction mechanism describes in detail the structural changes occuring in the process of a

chemical reaction, including which atoms and molecules are interacting, which bonds are broken

and formed, etc.

Breaking Covalent Bonds There are two main ways in which a two-electron covalent bond can be broken: homolytically and

heterolytically.

Homolytically: (Homo as in 'each atom is treated the same'). Each atom in the bond gets a single

election (diagram on the left)

Heterolytically: (Hetero as in 'each atom is treated differently'). Each atom in the bond (the one with

higher electronegativity) gets both electrons, and the other atom gets neither (diagram on the right)

Forming Covalent Bonds There are two main ways in which two-electron covalent bonds can be formed: homogenic and

heterogenic.

Homogenic: Each reactant donates a single electron (diagram on the left)

Heterogenic: A single reactant donates both electrons, and the other donates nothing (diagram on

the right)

Strengths of Acids and Bases The strength of organic acids is determined by three important structural effects: electronegativity,

orbital hybridisation, and resonance effects.

Electronegativity Electronegativity is a measure of the attractive force that an atom has for electrons - the higher the

electronegativity, the more strongly the atom attracts and holds electrons. These differences in

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electronegativity are the result of differences in the structure of electron orbitals in different

elements. In chemical reactions, electrons tend to be pulled away from atoms with low

electronegativity, and towards atoms with higher electronegativity.

Orbital Hybridisation For some atoms, some of the usual s,p,d orbitals sort of 'merge together' to form new, special hybrid

orbitals. These hybrid orbitals have different energy levels and result in different chemical properties

than would occur with just the regular orbitals. All hybrid orbitals have energy levels in-between

those of their constituent 'regular' orbitals (see energy diagrams below).

hybrid orbitals: these occur when the three 2p orbitals overlap with the single 2s orbital in a

tetrahedrally bonded carbon (e.g. in alkanes), to form four identical hybrid orbitals.

hybrid orbitals: these occur when only two of the three 2p orbitals combine with the single 2s

orbital to form three identical hybrid orbitals. The reason one 2p orbital is 'left behind' is

because these hybrid orbitals generally occur in alkenes, where one 2p orbital electron is required to

form the pi-bond between adjacent carbons. This leaves only 2p orbitals avaliable for hybridisation.

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hybrid orbitals: these occur when only one of the three 2p orbitals combines with the single 2s

orbital to form two identical hybrid orbitals. These are found in alkynes, where two 2p orbitals

are required for forming two pi-bonds, thus leaving only a single 2p orbital for hybridisation.

Resonance Resonance refers to the fact that some molecules, the electrons can be arranged in different ways.

This is not the same as isomerism, where the actual structural arrangement of the molecule is

different (i.e. the atoms themselves are in different positions, rather than just the electrons). In

different resonance forms of a given molecule, the structure of the molecule is the same each time,

but within the molecule the electrons are arranged slightly differently. In actual fact, resonance

forms don't exist as separate states 'by themselves'. Rather, the molecule really exists in what is

called a 'resonance hybrid', which is sort of like a mixture of all the possible resonance states.

In the example shown below, there are five different resonance states. The real molecule does not

actually exist in any single one of these states - rather it exists in a mixture of all of them at once.

Drawing the states separately like this is just a tool to help us understand what is happening - it

should not be taken literally!

Resonance allows electron orbitals to become more 'spread out' across the molecule (because the

electrons are shared across several different bonds rather than being localised to a single bond).

Electrons that are 'spread out' in this way have a lower potential energy (see diagram below).

Because their electrons have a lower energy level, molecules that experience resonance are

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generally more stable (less reactive) than molecules that don't experience resonance. This effect is

known as resonance stabalization.

Application to Strength of Acids and Bases The stronger an acid, the more readily it donates a proton. If we say that something is a strong acid,

this is the same as saying that its conjugate base is a very weak base - the conjugate base does not

react very readily. In summary: strong acids have stable conjugate bases.

Electronegativity: the more electronegative is the atom bearing the negative charge in the

conjugate base, the less reactive is that base (as the electron is more tightly held), and hence

the stronger is the acid.

More electronegative anion in conjugate base ⟹ stronger acid/weaker base

Orbital hybridisation: the greater the s character of the C-H bond that is broken during the

donation of a proton, the stronger that bond tends to be (as the s orbital is closer to the

nucleus). Stronger C-H bonds stabalise the conjugate base, thereby making the acid stronger.

Greater character of bond orbital in acid ⟹ stronger acid/weaker base

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Resonance effects: the more resonance forms the conjugate base has, he more stable it is,

and hence the stronger the corresponding acid will be.

More resonance forms of conjugate base ⟹ stronger acid/weaker base

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Electrophiles and Nucleophiles

Electrophiles Possess either a positive charge, or a polarised bond with a partial positive charge. In either case, the

concentration of positive charge causes them to be strongly attracted to negative charges, hence

they are 'electron loving'. Because they tend to accept a lone pair of electrons, electrophiles are also

lewis acids.

Nucleophiles Possess either a negative charge or a lone pair of electrons. In either case, the concentration of

negative charge causes them to be strongly attracted to positive charges, hence why they are

'nucleus loving'. Because they tend to donate a lone pair of electrons, nucleophiles are also lewis

bases. Examples of nucleophiles are shown below. Nucleophiles are reducing agents - they cause

reduction by themselves undergoing oxidation (losing surplus electrons). The best nucleophiles have

a lone pair of electrons and/or negative charge, but low electronegativity. This means they cannot

'hold on' to their negative charges very well, and so tend to more readily act as a lewis base (i.e.

donate a pair of electrons).

Acting as Both Some molecules can behave as either a nucleophile or an electrophile depending on what else they

are reacting with. For example, the methanol shown in the centre is reacting as a nucleophile to the

left, and an electophile to the right.

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Reactions Because they are essentially opposites, electrophiles and nucleophiles tend to react with one

another - this is just another way of describing an lewis acid-base reaction. Some examples are

shown below.

Alkyl Halide Reactions

Nucleophilic Substitution Reactions

Overview Nucleophilic substitution reactions are a very important type of reaction in organic chemistry. These

reactions are characterised by the fact that they always involve one nucleophile being substituted

for another nucleophile. There are two main types of nucleophilic substitution reaction: SN1 and

SN2. In either case, nucleophilic substitution reactions involve a nucleophile 'attacking' a carbon

molcule and displacing an atom or molecule called the leaving group. Since the leaving group carries

away an electron pair, it too is a nucleophile. Since one nucleophile has replaced another, these

reactions are called substitution reactions.

Essentially, the leaving group does not form as stable a bond with the substrate as the attacking

nucleophile, owing to its higher electronegativity and hence tendency to disassociate and 'keep its

lone pair'. Thus, if an alternative nucleophile with a lower electronegativity is present, it will tend to

preferentially bond to the substrate, resulting in the nucleophilic substitution reaction.

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Alkyl Halides Halides make good leaving groups, and so alkyl halides are particularly useful in organic synthesis

SN1 Reactions The rate of the SN1 reaction only depends upon the concentration of the substrate (i.e. the main

carbon molecule), and not on the concentration of the reagent (i.e. the new nucleophile that

displaces the leaving group). This makes SN1 reactions first-order processes, hence the '1' in the

name. The concentration of the product does not affect SN1 reactions because they occur in two

stages, only one of which is rate-limiting (i.e. one of the two stages occurs much more quickly than

the other, so only the slower one determines the rate of the overall reaction).

The two stages of an SN1 reaction are as follows:

1. The leaving group disassociates, leaving behind a positively charged carbon-based ion called

a carbocation

2. The new nucleophile molecule reacts with the carbocation

Because the reaction occurs in two stages, the reaction energy diagram has two 'humps', each

corresponding to the energy barrier needed to initiate each stage of the reaction. Note that the

second stage has a lower energy barrier, which is why it occurs more rapidly.

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SN2 Reaction The rate of the SN2 reaction depends upon both reactants (the substrate and the reagent), rather

than only the substrate as in the case of the SN1 reaction. This means that SN2 reactions are second-

order reactions, hence the '2' in the name. Unlike SN1 reactions, which involve two stages, SN2

reactions only have a single stage, as the breaking of old bonds and formation of new bonds occur

simultaneously. Since two distinct processes must occur simultaneously, the reaction rate will

depend on the rate of both of these processes, hence it will be a second order reaction.

Essentially, the reaction proceeds by the reagent molecule (the new nucleophile) bonding to the

carbon substrate from one side, briefly forming a high-energy transition state, followed by the old

nucleophile disassociating from the other side of the molecule.

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Because there is only one step to the reaction, the energy diagram has only a single hump. Note that

the energy peak is particularly high, as the transition state is particularly unstable, meaning that it

has very high energy.

Chirality and Reaction Type If the substrate under nucleophilic attack is chiral, this can lead, although not necessarily, to an

inversion of stereochemistry. This depends on whether the nucleophile participates in a frontside or

a backside attack. In a frontside attack, the nucleophile attacks the electrophilic center on the same

side as the leaving group. When a frontside attack occurs, the stereochemistry of the product

remains the same; that is, we have retention of configuration. In a backside attack, the nucleophile

attacks the electrophilic center on the side that is opposite to the leaving group, and there is

inversion of configuration.

Experimental observation shows that all SN2 reactions proceed with inversion of configuration; that

is, the nucleophile will always attack from the backside in all SN2 reactions.

Reaction Rates Substrate: In SN1 reactions, the more stable the carbocation intermediate, the faster the

reaction occurs. The more highly substituted the recipient carbon is, the more stable will the

intermediate be, and hence the faster will be the reaction

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The order is precisely the opposite for SN2 reactions, as these reactions have no carbocation

intermediate. Instead, the additional carbonyl groups 'get in the way' of the nucleophile.

This steric hindrance slows the rate of reaction.

Nucleophile: Stronger bases and lower electronegativities generally correspond with better

nucleophiles, and hence generally lead to a faster reaction rate. This is much less important

for SN1 than SN2 reactions, as the rate-limiting step in SN1 reactions does not involve the

nucleophile

Leaving group: the lower the potential energy of the bond electrons in the leaving group, the

more stable (and hence 'better') that leaving group will be. This means that highly

electronegative atoms make good leaving groups

The Role of the Solvent In order for the nucleophile to react with the carbon substrate, the nucleophile must come out of

solution. The more 'tightly' the nucleophile is held by the solution (i.e. the better is the solvent), the

more difficult it is for the nucleophile to come out of the solution, and hence the slower the reaction

proceeds.

Since nucleophiles are attracted to positive charges, protic solutions (i.e. solutions with lots of

protons avaliable for bonding, such as in -OH or -NH groups) tend to dissolve them well. Hence

protic solvents tend to slow the rate of SN2 reactions, while aprotic solvents (lacking an -OH or -NH

group).

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Nucleophilic Elimination Reactions Elimination reactions occur when a nucleophilic attacking species acts as a base instead of a

nucleophile. There are two main pathways by which elimination reactions can occur: E1 and E2.

E1 Mechanism The reaction occurs in two stages. First the carbon-halogen bond breaks to give a carbocation

intermediate. Second, the carbocation is deprotonated by a base to yield an alkene.

The reaction rate for an E1 reaction is determined solely by the concentration of the substrate. This

is the same as an SN1 reaction, as in both the rate limiting step is the departure of the leaving group.

Reaction energy diagram:

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E2 Mechanism The reaction occurs in a single stage. The C-H and C-X bonds break simultaneously, yielding the

alkene immediately with no intermediates. In the E1 reaction, the leaving group just sort of 'falls off'

by itself. In an E2 reaction, this does not occur. Instead, a strong base (nucleophile) is needed in

order to bind to the substrate and hence form an unstable transition state, before both the base and

the leaving group disassociate from the substrate, completing the reaction.

Also note that in E2 reactions, the leaving hydrogen and the leaving group (halogen) must be on

opposite sides of the molecule, as this arrangement permits the transitional state to have lower

energy. This so-called antiperiplanar requirement does not apply to E1 reactions.

The reaction rate is second order, because it depends on the concentration of both the substrate

and the base.

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Zaitsev's Rule When HX is eliminated from an alkyl halide, of all the possible products, the one with the most

highly substituted alkene predominates. This occurs because more highly substituted alkenes are

more stable, effectively because they have more 'space' to spread out their electrons (i.e. resonance

and inductive effects).

Types of Akyl Halide Reactions

Primary Alkyl Halides These react almost exclusively through SN2 or E2. Bulky nucleophiles/bases make E2 reactions more

likely, owing to increased steric hindrance in SN2 reactions.

Secondary Alkyl Halides These can react by any of the four mechanisms: E1, E2, SN1 or SN2.

Tertiary Alkyl Halides These tend to undergo E2 reactions when a strong base is used, but SN1 under neutral conditions.

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Alkene Reactions

Electrophilic Addition Reactions

Overview In organic chemistry, an electrophilic addition reaction is an addition reaction where, in a chemical

compound, a π bond is broken and two new σ bonds are formed. The substrate must always have a

pi bond, and hence will be relatively electron abundant - thus it tends to react with electrophiles

(positive charges). Since pi bonds are fairly weak, addition reactions tend to be exothermic (the

bonds formed afterwards are stronger).

Reaction Mechanism An electrophilic addition reaction proceeds in two stages:

stage 1: an electrophile (cation or positive dipole of a molecule) accepts an electron from

the double bond. This binds the cation atom to one of the carbons that was previously part

of the double bond, and leaves the other carbon one electron short, thus becoming a

carbocation

stage 2: the remaining anion (or former negative dipole) now has a lone pair, and so binds to

the carbocation left over from the original double bond

Thus, by the end of the reaction, one species has formed a bound with each of the carbon atoms

that were previously part of the double bond.

Asymmetric Alkenes An unsymmetrical alkene is one like propene or but-1-ene in which the groups or atoms attached to

either end of the carbon-carbon double bond are different.

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In this case, the reaction product will now be different depending on whether the electrophile binds

to the carbon on the left, or to the carbon on the right. In the example shown above, we could get:

Or we could get a different product:

Markovnikov's Rule So can we predict which reaction will occur? This question is answered by Markovnikov's rule, which

states that with the addition of a protic acid HX to an alkene, the halide (X) group becomes attached

to the carbon with more alkyl substituents (not counting hydrogen atoms).

The chemical basis for Markovnikov's Rule is the formation of the most stable carbocation during the

addition process. The addition of the hydrogen ion to one carbon atom in the alkene creates a

positive charge on the other carbon, forming a carbocation intermediate. The more substituted the

carbocation (the more bonds it has to carbon or to electron-donating substituents) the more stable

it is, due to induction and hyperconjugation. The major product of the addition reaction will be the

one formed from the more stable intermediate. This is the same reason why SN1 reactions occur

more quickly for highly-substituted substrates - they are more stable and so the reaction initiation

energy is lower.

One way of thinking about this is that in the process of reaching chemical equililbrium, hydrogen

ions bind to all of the possible carbon atoms on the substrate, forming a variety of different

carbocations. The more stable such a carbocation is, however, the more likely it is to persist for long

enough to complete the reaction by binding with a halide. Carbocations with more substituents are

more stable, hence they survive longer, and hence are more likely to be involved in stage 2 of the

reaction.

Nucleophilic Addition Reactions

Overview A nucleophilic addition reaction is an addition reaction where in a chemical compound a π bond is

removed by the creation of two new σ bonds by the addition of a nucleophile. The basic result of the

reaction is simply that a nucleophile and a hydrogen are added to the molecule, disrupting the CO

double bond, forming some new functional group.

Reaction Mechanism The driving force for the addition to alkenes is the formation of a nucleophile X that forms a covalent

bond with an electron-poor unsaturated system -C=C- (step 1). The negative charge on X is

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transferred to the carbon-carbon bond. In step 2 the negatively charged carbanion combines with a

proton (positive charge) to form the second covalent bond.

Cyanide Anion

Grignard Reagents Grignard reagents are molecules used to add to a carbonyl group in an aldehyde or ketone (i.e.

across a C-O double bond, meaning that it is a nucleophilic addition reaction). This reaction is an

important tool for the formation of carbon–carbon bonds. Grignard reagents form via the reaction

of an alkyl or aryl halide with magnesium metal, so they always contain Mg, X, and an R group.

After the gringnard reagent has displaced the double bound, the MgX substituent can be removed

by addition H+/H2O to the reaction, which leaves a H bonded to the O in place of the MgX.

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Acetylide Anions Acetylide ions are very useful in organic chemistry reactions in combining carbon chains, particularly

addition and substitution reactions. One type of reaction displayed by acetylides are addition

reactions with ketones to form tertiary alcohols.

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Addition Followed by Elimination Carbonyl compounds react with nucleophiles via an addition mechanism: the nucleophile attacks the

carbonyl carbon, forming an intermediate. After the tetrahedral intermediate forms, it collapses,

recreating the carbonyl C=O bond and ejecting the leaving group in an elimination reaction. As a

result of this two-step addition/elimination process, the nucleophile takes the place of the leaving

group on the carbonyl compound by way of an intermediate state that does not contain a carbonyl.

Both steps are reversible and as a result, nucleophilic acyl substitution reactions are equilibrium

processes. Because the equilibrium will favor the product containing the best nucleophile, the

leaving group must be a comparatively poor nucleophile in order for a reaction to be practical.

Common carbonyl substrates:

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Electrophilic Aromatic Substitution

Overview Benzene is already very stable because of its resonance stabalised ring, so it tends not to react with

weaker electrophiles. It will react, however, with strong electrophiles, or in the presence of catalysts

(a Lewis acid) that is able to ionise or polarise molecules into stronger electrophiles.

Reaction Mechanism The basic process of this reaction is that first, an electrophile will 'steal' an electron from one of the

double-bonded carbons in the benzene, causing the electrophile to bind to that carbon. In the

second step, this same carbon (which now is bonded to four atoms), loses its hydrogen atom ,

thereby restoring the double-bond and hence the aromaticity of benzene.

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Activation Energy The complete delocalisation is temporarily broken as X replaces H on the ring, and this costs energy.

However, that energy is recovered when the delocalisation is re-established. This initial input of

energy is simply the activation energy for the reaction.

Substituent Effects Existing substituents on a benzene ring can affect the reaction in a number of ways. Substituent

groups can be classified as to whether they are electron donating or withdrawing and are known

as activating and deactivating respectively.

Electron-donating groups are activating groups, because they normally have a lone pair or fractional

negative charge on an atom directly bonded to the ring. Activating groups donate electrons to the

ring, thereby making the carbocation intermediate more stable (lower energy), and hence lowering

the activation energy for the substitution reaction as a whole.

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Electron-withdrawing groups, which are generally electron deficient with a positive fractional charge

on the atom bonded directly to the ring, remove electrons from the benzene ring, thereby making

the carbocation intermediate less stable, hence raising the activation energy and making the

reaction less likely.

Substitution patterns Substituent groups can also affect the preferred shape of the product molecule. Some groups

promote substitution at the ortho or para positions, while other groups increase substitution at the

meta position. These groups are called either ortho-para directing or meta directing.

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Friedel-Crafts Reactions The Friedel–Crafts reactions are a set of reactions developed by Charles Friedel and James Crafts in

1877 to attach substituents to an aromatic ring. Friedel–Crafts alkylation involves the alkylation of an

aromatic ring with an alkyl halide using a strong Lewis acid catalyst.

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Other Reaction Types

Hydrolysis Reactions Hydrolysis reactions involve the cleavage of large molecules by the addition of water. More broadly,

these can be thought of as a nucleophilic substitution reaction - the water replaces a leaving group.

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Reduction Reactions Reduction of organic molecules involves either increasing H content, or decreasing O, N or halogen

content. Usually reduction requires a noble metal catalyst, such as Pd, Pt or Ni.

Another common class of reduction reactions involves the use of the following species as sources of

hydrogen for the reduction:

Often this reaction (called hydride reductions) involves adding a hydrogen across the C=O double

bound in ketones, aldehydes, and esters.

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This can be a multi-stage process, as illustrated in the following reaction:

Oxidation Reactions Oxidation is the reverse of reduction. It involves a decrease in H content, or an increase in O content.

Common oxidation agents are given below: