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B15

Medicines by Design..

Revision of reagents, conditions and reaction types.

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Aliphatic chemistry reagents and conditions Aliphatic chemistry reaction types Aromatic chemistry reagents and conditions Aromatic chemistry reaction types Key words and definitions.

X10

SCl2 O

Heat + reflux

NaCN in ethanol/H2OHeat + reflux

Dil H

2 SO4

Heat + reflux

A10. Aliphatic Reactions. Add the reagents and conditions.

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1

2

3

4

4

5

6

6

7

7

8

9

9

9

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X12

A12. Aliphatic reagents and conditions

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X11

Al2O3

300oC

K2Cr2O7(aq)/dil H2SO4

heat + reflux

NaBH4

Room temp

K2Cr2O7(aq)/dil H2SO4

heat + refluxR’OH/conc H2SO4 catHeat + reflux

NaO

H(aq)

Heat + reflux

SCl2 O

Heat + reflux

H2 /N

i cat150

oC + 5 atm

Br2(l)sunlight

NaCN in ethanol/H2OHeat + reflux

Con

c N

H3

Hea

t + re

flux D

il H2 SO

4

Heat + reflux

Conc NH3

Room temp

R’N

H2

Roo

m te

mp

NaBr(s) + conc H2SO4

heat + reflux

Conc HBr

Room

temp

R’OH Roo

m temp

A11. Aliphatic reagents and conditions

Dil HCl or H2SO4 or NaOHHeat + reflux

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X13

H2 /N

i cat150

oC + 5 atm

A13. Aliphatic Reactions. Add the reaction types.

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X14

Elimination or dehydration

Oxidation

Reduction

OxidationEsterification orcondensation

Nucleophilic

substitution

Addition or

hydrogenation

Radicalsubstitution

Nucleophilicsubstitution

Nuc

leop

hilic

su

bstit

utio

n

Hydrolysis

Nucleophilic substitution oracylation

Nuc

leop

hilic

Subs

titut

ion

orac

ylat

ion

Nucleophilic substitution

A14. Aliphatic Reaction types

Hydrolysis

Nucleophilic substitution oracylationElectrophilic

addition

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A1. The addition reactions of alkenes with the following: bromine, hydrogen in the presence of a catalyst, hydrogen bromide, and water in the presence of a catalyst.

CI 12.2

Ethene is unsaturated it has a double C to C bond. It undergoes electrophilic addition reactions in which another molecule is added on. A saturated compound is produced.

a. Ethene with bromine (g) or (l) or dissolved in an organic solvent. Ethene will decolourise orange bromine; it reacts rapidly to form a colourless compound. This

occurs at room temperature.

1,2-dibromoethane (colourless)

b. Ethene with Bromine water Br2(aq)

(orange) a bromoalcohol (colourless)

Bromine water (bromine dissolved in water) is more convenient and safer to use as a test of unsaturation, than bromine(g) or bromine(l) or bromine dissolved in an organic solvent such as cyclohexane.

R(reagent) is Br2(g) or Br2(l) or Br2 in an organic solvent. (NB Salters includes catalysts in this

category if required)

C

(conditions) are room temperature. (NB Salters includes pressures here if required).

R(reagent) is Br2(aq)

C(conditions) are room temperature.

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C. Ethene with concentrated hydrobromic acid, HBr(aq)

Bromoethane (now saturated)

d. Ethene with hydrogen(g) Hydrogenation

ethane

e. Ethene with water H2O(g) (it is steam at 3000C) The catalyst is phosphoric acid absorbed onto silica ( I imagine silica as being like pure white sand and that it is soaked in the acid which is a liquid).

ethanol

Note: Reactions a,b,c,d, and e are all examples of addition reactions. Reactions a, b, c and e are examples of electrophilic addition reactions. Reaction d involves a catalyst and has a different mechanism.

Rconc. HBr(aq)

C room temperature.

RH2(g) and Ni (or Pt) catalyst, finely powdered

C 1500C and 5 atm with the Ni. (or room temp. and pressure with the Pt).

NB Pt is white gold:- very expensive

RH2O(g) cat. Phosphoric acid absorbed onto silica.

C 3000C and 60 atmospheres pressure.

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The mechanism of the electrophilic addition reaction between bromine and alkenes.

CI 12.2

Mechanism for reaction in a above

H

H

H H

C C+

Br

H

H

Br

C CH H

BrBr1,2-dibromoethane

curly arrows

show movement of a pair of electrons.

The bromine molecule is polarised i.e. it has a + and a - atom, like when the bond is polar. This happens because the electrons in the Br2 molecule are repelled by the electrons in the C=C.

The Br + end now acts as an electrophile. Electrophiles are attracted to a negatively charged region (the C=C is made up of 4 electrons) and go on to accept a pair of electrons (2 points in the definition).

The carbocation has a C with a positive charge. That C had a half share of the two electrons in the bond, which was broken. It now has no share

of that pair.

It is now a C atom with one less e- so it has a single + charge.

The bromide ion is written One of the lone pairs has come from the bond in the Br2 molecule. It had a share of the bonding pair, but now has both electrons.

It has now overall gained an electron, so the Br atom now has a - charge.

Then we have the next step:

This is electrophilic addition. It is very important that you understand this mechanism and are able to explain it. The other reactions of ethene proceed by a similar mechanism.

NB philic means likephobic means hate

H

a carbocation and a bromide ion

Br

Br

Br

C C

H

HHC C

+H

Br

HH

H+

Br

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A2. The dehydration of alcohols to form alkenes.

CI 13.4

In a dehydration reaction, a molecule of water is lost. Sometimes, this is called an elimination reaction. Saturated Unsaturated This is the reverse of an addition reaction.

E.g. CH3CH2OH CH2=CH2 + H2OReagents: Ethanol passed over alumina (Al2O3) catalyst.Conditions: 300oC

NB Phenols and carboxylic acids do not undergo dehydration reactions.

The meaning of the term elimination reaction.

CI 13.4

In an elimination reaction, a small molecule (e.g. water) is lost. Dehydration of alcohols are elimination reactions.

Write 2 equations for the elimination of water from propan-1-ol. In the first, use full structural formulae. In the second, use skeletal formulae.

What are the alternative reagents and conditions for this reaction?

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A3. The reaction of alkanes with halogens.CI 6.3

Examples: CH4 + Cl2 CH3Cl + HCl :equation (1)C6H14 + Br2 C6H13Br + HBr

These are both radical substitution reactions where the halogen replaces hydrogen. This type of reaction leads to a mixture of halogen substituted products because we cannot control the radicals that are produced.

Mixture of products The reaction of methane (CH4) with chlorine in the presence of sunlight proceeds via a radical chain reaction. The overall equation for the reaction is equation (1) above.

Complete the reaction mechanism below:

Initiation: Cl2 h 2Cl.

Propagation:CH4 + Cl. CH3. + HClCH3. + Cl2 CH3Cl + Cl. (chloromethane made)CH3Cl + Cl. CH2Cl. + HClCH2Cl. + Cl2 CH2Cl2 + Cl. (dichloromethane made)

Termination:

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A4. Nucleophilic substitution reactions of the halogenoalkanes with hydroxide ions and ammonia.CI 13.1, Act A4.1b

The feature of a halogenoalkane molecule that allows it to undergo substitution reaction is the presence of a polar bond between the halogen atom and the carbon atom to which it is bonded. The halogen atom is slightly negatively charged and the carbon atom is slightly positively charged. This carbon atom is attacked by nucleophiles.

Why is the carbon – halogen bond polar?

Complete this table for 2 common nucleophiles:Formula Structure

(inc. lone pairs)Reaction Organic product

OH - _ .. : O : H ..

R-X + OH- R-OH + X- Alcohol

NH3 Amine

The mechanism of nucleophilic substitution in halogenoalkanes.CI 13.1

In general:

where X – is any nucleophile and the curly arrow shows the movement of a pair of electrons.The C – Hal bond will break heterolytically !

-+

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A5. An outline of the preparation of a halogenoalkane from an alcohol.Act A4.2

One way to make a halogenoalkane is to start with an alcohol and replace the – OH group by a halogen atom.

Reaction in Activity A4.2:

2 – methylpropan – 2 – ol 2 – chloro – 2 methylpropane

This is an example of nucleophilic substitution – the alcohol group is first protonated in the strongly acid solution before it can be displaced by the Cl – nucleophile ( water is lost).

Give the mechanism for this reaction: (CI 13.1, page 303 may help)

R

C

NaBr(s) and concentrated H2SO4

Heat and reflux

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A6. Amines can act as nucleophiles with acyl chlorides

ammonia / amines react with acyl chlorides:

ammonia + acyl chloride primary amide + HX

primary amine + acyl chloride secondary amide + HX

These are nucleophilic substitution reactions.

Complete the following equations;

These reactions are very vigorous even at room temperature.

The C has two more electronegative groups attached so they are very attractive to nucleophiles e.g. NH3, amines.

The reactions of amines and acyl chlorides are sometimes called acylation reactions.

CI 13.8

-

-

+

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A7. Ester formation from alcohols or phenols

Esters are named after the alcohol and the acid from which they are made:

Complete the following table:

Acid Alcohol Resulting Ester

CI 13.5

CO

O CH

H

H

Hmethyl methanoate

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Examples:

Acid + alcohol ester + waterwater

a.

b.

c.

N.B. All of these reactions in which esters are made are reversible reactions. The forward reaction is called esterification The backward reaction is called hydrolysis. In Act WM2, an ester was hydrolysed. The catalyst

was sodium hydroxide solution.

When making an ester using a phenol rather than an alcohol, a more vigorous reagent than a carboxylic acid is needed. The OH group in a phenol is less reactive than the OH group in an alcohol.

Method 1

Phenol + carboxylic acid ester +water

(conc. H2SO4 catalyst and heat under reflux is needed even with an alcohol).

CO

O HCH

3C

O

OCH

3C H

3

O HH+ +

ethanoic acid methanol methyl ethanoate water+ +

+ +

CO

O HCH

3C

O

OCH

3C H

2C H

3

O HH+ +

ethanoic acid ethyl ethanoate waterethanol

CH

OHC

H

H

H

H

CO

OHCH3 + +

+ +propanol water

CH3 CO

O CH2 CH2 CH3

ethanoic acid propyl ethanoate

O HHC C C OH

HH

H

H H

H

H

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Method 2

Phenol + acid anhydride ester + carboxylic acid

(This does not need heat and reflux. It is reactive but not too dangerous. This method was used to make aspirin in WM.)

Method 3

Phenol + acyl chloride ester + hydrochloric acid

(Faster but ethanoyl chloride is toxic and hazardous as it is so very reactive.)

Both acid anhydrides and acyl chlorides are called acylating agents:

-OH on alcohol or on phenol is replaced by in the ester. This is an acyl group.

Why do you think both methods 2 and 3 must be carried out in the absence of water?

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A8. The hydrolysis of esters

The reverse of esterification is hydrolysis. Hydrolysis is bond breaking involving water.

Ethyl ethanoate + water ethanol + ethanoic acid

On hydrolysis, the sweet smell of the ester disappears. To speed up this reaction NaOH(aq) is often used, when heating under reflux. This reaction was used in the hydrolysis of Oil of Wintergreen in WM.

A9. The following reactions involving aldehydes and ketones: formation by oxidation of alcohols, oxidation to carboxylic acids and reduction to alcohols.

CI 13.7

Recognising aldehydes and ketones.

Aldehydes and ketones are both carbonyl compounds which have the carbonyl group:

CI 13.5

What ion is produced instead of ethanoic acid if NaOH(aq) is used as a catalyst? Give name and full structural formula.

What needs to be added now to produce ethanoic acid from the ethanoate ion?

CO

OCH

3C H

2C H

3

CH

OHC

H

H

H

H

CO

O HCH

3O HH+ +

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Aldehydes are made when a primary alcohol is oxidised.

examples: (2 C’s => eth suffix al)

(3 C’s => prop, suffix al)

In aldehydes the carbonyl group is always on the end of the C chain so no number is required in the name.

Ketones are made when a secondary alcohol is oxidised.

examples:

Formation of aldehydes and ketones from alcohols.

Remember a triangle!

1ry alcohol oxidation aldehyde oxidation carboxylic acid2ry alcohol oxidation ketone 3ry alcohol

A good oxidising agent is acidified potassium dichromate (VI) solution.

Here is the half equation showing what happens to the dichromate ions:Cr2O7

2- + 14H+ + 6e- 2Cr3+ + 7H2O 6+ (acid) 3+orange greenThis is the half equation for the oxidation of ethanol:CH3-CH2-OH + H2O CH3CHO + 2H+ + 2e-

Combine the 2 half equations above and write an overall equation for the redox reaction:

(The carbonyl group is midway along the carbon chain. A number may be required to show which C atom has the carbonyl group)

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Definitions of oxidation are: Gain of oxygen Loss of hydrogen Loss of electrons Increase in oxidation number.

Give four definitions of reduction:

Is the chromium in the half equation above oxidised or reduced?

A closer look at the reaction of the 1ry alcohol:

1ry alcohol a aldehyde b carboxylic acid

Why are both of these steps described as oxidation?

a.

b.

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A closer look at the reaction of a 2ry alcohol:

2ry alcohol ketone carboxylic acid

Why doesn’t oxidation of the ketone occur?

A closer look at the reaction of a 3ry alcohol:

3ry alcohol ketone

Why doesn’t oxidation of a 3ry alcohol occur?

NB. Phenols and carboxylic acids are not oxidised either!

It is important that you can quote the reagents and conditions for these oxidations:Reagents – K2Cr2O7(aq), dilute HCl(aq) or dilute H2SO4(aq)Conditions – Heat and reflux.If oxidation occurs, there will be a colour change from orange to green.

Reduction of carbonyls to alcohols.

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Aldehyde 1ry alcohol Ketone 2ry alcohol

Give the formulae of the carbonyl componds which would be reduced to these alcohols:

R = NaBH4(aq)C = room temperature

Name the reagent:

This would be reduced to the alcohol on the right…..

This would be reduced to the alcohol on the right…..

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R7

11

23.

H2(g), Ni cat300oC, 30 atm.

45

6

6

Sn + conc HClHeat + reflux

Aromatic. Add the reagents and conditions.

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25

R8

Cl2(g), AlCl3 cat room temp/ anhydrous

Br2(l), FeBr3 catroom temp.

conc. HNO3, conc. H2SO4 cat<55oC.

conc. H2SO4.heat + reflux.

H2(g), Ni cat300oC, 30 atm.

RCl(l), AlCl3 catheat + reflux/ anhydrous.

RCOCl(l), AlCl3 cat.heat + reflux/ anhydrous

NaNO2(aq)/dil HCl<5oC

alkaline phenol<5oC

Sn + conc HClHeat + reflux

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Aromatic reagents and conditions

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R9

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Aromatic reagents and conditions

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C10

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Aromatic Reaction types Run off a hard copy of

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C11

Electrophilic substitution

Electrophilic substitution

Electrophilic substitution

Electrophilic substitution

Hydrogenation

Electrophilic Substitution or Friedel Crafts alkylation

Electrophilic Substitution or Friedel Crafts acylation

Diazotisation

Coupling reaction

Reduction

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Aromatic reaction types

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R1. Halogenation of the ring in arenes.

CI 12.4.

What would the formula of the product have been if addition had occurred rather than substitution?

+

-

The FeBr3 helps to polarise the bromine by accepting a lone pair of electrons from one of the bromine atoms.

The bromine molecule is polarised as it approaches the benzene ring.

Br+

Br-

The bromine molecule is so polarised that it splits.

Br+ becomes bonded to a ring C and H+ is lost. Br+ is an electrophile: Has a + charge Attracted to electron rich centre Accepts pair of electrons to form

a dative covalent bond.

The H+ reacts with the FeBr4-. FeBr3 is regenerated as it is a catalyst

in the reaction.

R

C

Br2(l) and either FeBr3 or Fe(s)

Room temperature.

E C6H6 + Br2 C6H5Br + HBr

Electrophilic Substitution……

Why does the benzene attract electrophiles?

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Chlorine reacts in a similar way to bromine. Complete the mechanism:

+

-

The AlCl3 helps to polarise the chlorine by accepting a lone pair of electrons from one of the chlorine atoms.

The chlorine molecule is polarised as it approaches the benzene ring.

Cl+

Cl-

The chlorine molecule is so polarised that it splits.

Cl+ becomes bonded to a ring C and H+ is lost. Cl+ is an electrophile: Has a + charge Attracted to electron rich centre Accepts pair of electrons to form

a dative covalent bond.

The H+ reacts with the AlCl4-. AlCl3 is regenerated as it is a catalyst

in the reaction.

R

C

Cl2(l) and AlCl3(s)

Room temperature, anhydrous.

E C6H6 + Cl2 C6H5Cl + HCl

Electrophilic Substitution……

AlCl3

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R2. The nitration of benzene.

CI 12.4.

Why do we say that the sulphuric acid is a catalyst?

Electrophilic substitution.

R

E C6H6 + HNO3 C6H5NO2 + H2O

C

Conc. Nitric acid and conc. sulphuric acid as a catalyst.

< 55oC. Explain why…..

The nitrating mixture

NO2+ is an electrophile.

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R3. The sulphonation of benzene.

CI 12.4.

.

E

Electrophilic substitution.

C

R Conc. sulphuric acid

Heat and reflux

Draw the structural formula of the electrophile and name it:

Name the organic product of this reaction:

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R4. The Friedel-Crafts alkylation of benzene.

CI 12.4

Why Friedel-Crafts?

Why alkylation?

Give the reagents and conditions:

How would you do this experiment differently if you wanted to make ethylbenzene rather than methylbenzene?

Electrophilic substitution

E

C

R

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R5. The Friedel-Crafts acylation of benzene.

CI 12.4.

In these reactions, an acyl group is introduced into the benzene ring.

Acyl chlorides also have acyl groups in. Draw the full structural formula of propanoyl chloride and also circle the acyl group:

Friedel-Craft reactions are so useful to Chemists because they provide a way of adding carbon atoms to the benzene ring.

E

R

C

Give the reagents:

Give the conditions:

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R6. The formation of azo dyes by coupling reactions involving diazonium compounds.

CI 13.10.

Coupling reactions:

Diazonium salt + Coupling agent Azo compound

Diazonium salts:

A typical diazonium salt is benzenediazonium chloride;

This is made from phenylamine. The reaction is called diazotization.

R = NaNO2(aq) and dilute HCl

Name the reagents:

Why does the temperature have to be less than 5oC?

Azo compounds:

This is an azo compound. Circle the azo group:

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If R and R’ are aromatic then the azo compound is more stable than if they were aliphatic. This is because the azo compound then has an extended delocalised system of electrons. Aromatic azo compounds are coloured and used as dyes.

The coupling agent reacts with the diazonium salt to make the azo compound.

The coupling agent is another compound containing a benzene ring e.g. phenol or phenylamine.

Name the 2 organic reagents above…..

R = The phenol is in an alkaline solution for this reaction. C = At temperature less than 5oC, the coloured azo compound is formed immediately.

Is the diazonium salt an electrophile or a nucleophile here?

What colour is the azo compound above?

Write the equation for the formation of another azo compound:

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Key Words

Acylation The introduction of an acyl group, RCO-, using an acyl chloride.Typical of alcohols, amines, ammonia and arenes.

Addition The addition of atoms or groups of atoms across a double bond.Typical of alkenes, aldehydes and ketones.

Alkylation The introduction of an alkyl group, R, using a chloroalkane.Typical of arenes.

Carbocation An organic molecule containing a carbon atom with a + charge.Intermediates in the electrophilic addition reactions of alkenes.

Condensation A reaction in which two molecules join together and a small molecule such as H2O or HCl is eliminated. An example is the formation of an ester.

Coupling reaction The reaction between a diazonium ion and another aromatic compound to form an azo compound, R-N=N-R’Used to make azo dyes.

Dehydration A term sometimes used to describe the elimination of a water molecule from an alcohol to form an alkene.

Diazotisation The formation of a diazonium salt from an aromatic amine.

Electrophile Positive ion or molecule with + Attracted to an electron rich centre Accepts a pair of electrons to make a dative covalent

bond.

Electrophilic addition Typical of alkenes.

Electrophilic substitution

Typical of arenes since delocalisation is retained.

Elimination The loss of atoms or groups of atoms to produce an unsaturated compound.Typical of 1ry and 2ry alcohols.

Esterification A rection in which an ester is formed from an alcohol and a carboxylic acid.

Friedel Crafts acylation

The introduction of an acyl group, RCO-, into a benzene ring.Named after it’s discoverers.

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Friedel Crafts alkylation

The introduction of an alkyl group into a benzene ring.Named after it’s discoverers.

Hydrogenation The addition of hydrogen atoms across a C=C.

Hydrolysis A bond breaking reaction involving water, often catalysed by dilute acid or alkali.Typical of esters, amides and nitriles (R-CN).

Nucleophile A negative ion or a molecule with a lone pair of electrons Attracted to a positive/electron deficient centre Donates a pair of electrons to form a dative covalent bond.

Nucleophilic addition Typical of aldehydes and ketones.

Nucleophilic substitution

Typical of halogenoalkanes.

Oxidation Gain of oxygen Loss of electrons Loss of hydrogen Increase in oxidation numberTypical of 1ry alcohols, 2ry alcohols and aldehydes.

Radical Atom or molecule with an unpaired electron. These are very reactive.

Radical substitution Typical of alkanes.

Reduction Loss of oxygen Gain of electrons Gain of hydrogen Decrease in oxidation numberTypical of alkenes, aldehydes and ketones.

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