Reaction Mechanisms

Question 0

Define the term electrophile

Answer 0

An electron deficient species that reacts by accepting electrons In order to attain a filled valance shell. Can either be a positively charged species or a neutral species

Question 1

Define Homolytic and heterolytic reactions.

Answer 1

Homolytic- bond breaking in which the bonding electron pair is split evenly between the products. E.g radicals (single headed arrow indicates movement of one electron)

Heterolytic- When one atom leaves with all of the previously shared electrons and the other atom gets none of them. ( double headed arrow indicates movement of two electrons)

Question 2

Define the term nucleophile

Answer 2

A nucleophile has electrons available for donation to electron deficient centres. A nucleophile atom donates two electrons if it is either negatively charged, or neutral but carrying a non bonding pair of electrons.

Question 3

Explain the importance of mechanisms and synthetic transformations

Answer 3

1) many drugs are prepared synthetically, different isomers have different properties so we must be able to control which isomer is prepared for useful biological data to be obtained.

2) many synthetic transformations allow the spacial arrangement of groups to be defined, or specific functional groups to be introduced , for probing drug receptor interactions. Drug discovery programmes may require a specific isomer E.g. R or S
- introduction of the alkene functionality can also be useful for the rigidification of flexible chains. By adding a double bond there is less flexibility. Alkene rigidity can dictate the shape of the molecule and the interactions with binding pockets.

3) synthetic chemistry can be used to remove certain functional groups, to probe the importance of that functional group for drug-receptor binding.

Question 4

What is a substitution reaction

Answer 4

A reaction where one group is substituted for another.

Replacement of one functional group by another at sp3 hybridised carbon is referred to as aliphatic substitution

Good leaving groups are those that firm stable ions or neutral molecules after they leave the substrate.

Question 5

What is an elimination reaction

Answer 5

Elimination reactions Involve the removal of a molecule of two atoms or groups without them being replaced by other atoms or groups.

Question 6

What is an SN1 reaction

Answer 6

SN1 reactions involve the replacement of a leaving group by a nucleophile via a unimolecular process.

• Rate = k [ starting material A) , rate is only dependent upon the concentration of the alkyl substrate and is independent of nucleophilic concentration
• for SN1 reactions to occur the molecule must have a good leaving group and also a structure in which the positively charged carbon is suitably stabilised.

Question 7

Outline the stereochemical consequences of SN1 reactions

Answer 7

1) the carbon atom of the carbonation is planar. The bonding electrons are in sp2 orbitals and there is an empty p-orbital . So the nucleophile can attack from either face of the carbonation, thus the product will be a mixture of two enantiomers.
2) as there is usually an equal probability of attack on either face, a racemic mixture results.

Question 8

Define the terms enantiomer and racemic

Answer 8

Enantiomer- stereoisomer which is related as object and mirror image. Non superimposable- R or S

Racemic: equal quantities of each enantiomer.

Question 9

Describe what SN2 reactions are

Answer 9

1) SN2 reactions are single step processes in which attack by the nucleophile and departure of the leaving group occur simultaneously.
2) nucleophilic attack at the carbon centre occurs in a direction co linear with the bond being broken.
3) the reaction occurs via a penta coordinate trigonal bipyramidal transition state to give a product in which the configuration of the carbon has been inverted
4) Rate = K [Nu-] [starting material A]

Question 10

Explain the major difference between Sn1 and SN2 reactions

Answer 10

SN2 reactions proceed in one step via a transition state whilst SN1 reactions proceed in two steps via an actual carbonation intermediate.

• Sn1 planar carbonation intermediate
• Sn2 transition state

Question 11

Why does it matter if a reaction is Sn1 or Sn2

Answer 11

1) stereochemical consequences of the two reactions are different
- Sn1 racemic mixture
- Sn2 one stereoisomer

Question 12

Describe the factors that will influence weather a reaction proceeds via an Sn1 or Sn2 pathway.

Answer 12

1) the nature of the carbenium ion that could form via an SN1 reaction
2) steric effects
3) the nature of the nucleophile
4) the nature of the leaving group
5) the nature of the solvent

Question 13

Explain what hyperconjugation is

Answer 13

Stabilisation through the sigma bond framework

Order of carbonation stability- primary< tertiary

Question 14

Describe how steric effects can influence wether a reaction proceeds via an Sn1 or Sn2 pathway.

Answer 14

1) for an SN2 reaction the approach of the nucleophile and formation of the transition state us sterically hindered if the central C atom carries bulky substituents- thus SN2 reactions are favoured for primary substrates, and disfavoured for tertiary substrates.

Question 15

Describe how the nucleophile can influence wether a reaction proceeds via an Sn1 or Sn2 pathway.

Answer 15

1) the rate of an SN2 reaction shows a first order dependence on the nucleophile, and hence the rate of the reaction is affected by the nature of the nucleophile.
Sn2 - Rate = k [nucleophile] [substrate]
Sn1 - Rate = k [ substrate]
2) an anion is a better nucleophile than the uncharged conjugate acid
3) strong bases are good nucleophiles
4) for SN2 reactions the stronger the nucleophile the more the reaction will be promoted.
5) nucleophilicity is found to be influenced by the size of the attacking atom in the nucleophile , at least for comparisons within the same group or subgroup of the periodic table. - the larger the atom/group the better it will be as a NU-

Question 16

Describe how the leaving group can influence wether a reaction proceeds via an Sn1 or Sn2 pathway.

Answer 16

important for both Sn1 and SN2 reactions as the RDS in both mechanisms involves loss of the leaving group.
Factors influencing the ability of the leaving group to act as a leaving group include:
1) the strength of the R-Y bond
2) the polarisability of the bond
3) the stability of Y-
4) the degree of stabilisation, through solvation, of the forming Y- for either Sn1 or Sn2
5) nucleophilic substitution reactions are very difficult for leaving groups attached to unsaturated carbons. In these cases the reason for poor reactivity are more electrostatic than steric. Since the nucleophile is repelled by electrons of the unsaturated system. - not all molecules with good leaving groups undergo Sn1 or SN2 reactions.

Question 17

Describe how solvent effects can influence wether a reaction proceeds via an Sn1 or Sn2 pathway.

Answer 17

1) for SN1 reactions polar solvents will favour formation of the carbonium ion, and hence favour the SN1 reaction.
2) for SN2 reactions, solvent is important but in a different way. The nucleophile is involved in the RDS, but the nucleophile can be solvated by polar protic solvents, reducing its nucleophilicity. Thus polar aprotic solvents are often used to dissolve the ionic nucleophiles , but not reduce their nucleophilicity by solvation .
3) it is sometimes possible to alter a reaction pathway from Sn2 to Sn1 by increasing the solvent polarity and ion-solvating ability of the solvent. Likewise it is sometimes possible to alter a reaction pathway from Sn1 to Sn2 by transferring from a hydroxylic to a polar, non-protic solvent (e.g. DMSO.)

Question 18

Describe what happens in an elimination reaction and explain how this is different from substitution reactions.

Answer 18

1) nucleophilic substitution reactions can be considered to compete with elimination reactions.
2) in a nucleophilic substitution, the nucleophile attacks a carbon atom and a leaving group is lost from that carbon atom.
3) in elimination reactions the nucleophile attacks hydrogen instead of carbon, and the leaving group on an adjacent carbon is lost.

Question 19

Describe the E1 mechanism

Answer 19

The H-C and C-Y bonds can be broken separately in two steps processes. If the C-Y bond is broken first a carbonation intermediate is involved.

The RDS for both E1 and SN1 reactions are the same - first order and only dependent on the concentration of the substrate
Rate= K [substrate A]

Question 20

Outline the similarities between E1 and E2 reactions

Answer 20

1) in both cases, we form a new C-C Pi bond , and break a C-H bond and a C-(leaving group) bond
2) in both reactions , a species acts as a base to remove a proton, forming the new Pi bond
3) both reactions are favoured by heat

Question 21

Compare E1 and E2 reaction mechanisms

Answer 21

1) E1 is unimolecular (depends on concentration of substrate) VS E2 is bimolecular ( depends on concentration of both substrate and base)
2) E1 reactions form a carbocation VA E2 reactions no carbocation
3) E1 does not require a strong base VS E2 requires a strong base
4) E1 stereochemistry no requirement VS E2 leaving group must be anti to hydrogen removed

Question 22

Explain the E2 mechanism

Answer 22

1) the H-C and C-Y bond breaking is concerted, a one step process occurs which passes through a single transition state.
2) Rate = K [substrate A] [Base] second order kinetics reaction affected by the strength of the base employed.

Question 23

Outline the stereoselectivity in E2 reactions.

Answer 23

1) there is an advantage to H, Cβ, Cα, Y and the base B lying in the same plane during elimination since the Pi orbitals that are developing on Cβ and Cα as H+ and Y- depart will be parallel to each other and will be capable of maximum overlap in forming the Pi bond.
2) for acyclic molecules, elimination could be seen as taking place from one or other of two limiting conformations Antiperiplanar ( H & Y opposite sides) or synperiplanar (H and Y on the same side) arrangements. Antiperiplanar lower energy more stable while synperiplanar higher energy less stable

Question 24

Explain why Antiperiplanar eliminations are favoured

Answer 24

1) elimination occurring from the lower energy staggered conformer rather than from the higher energy eclipsed conformer. Staggered - every bond lies between bonds on adjacent C. Thus there will be less electron repulsion leading to more stability
2) the attacking base and the departing leaving group being as far apart as possible in the TS for anti-periplanar elimination. Less steric hinderance in the TS leading to the product.

Question 25

Describe the difference between Stereospecific reactions and Stereoselective reactions.

Answer 25

A stereospecific reaction is one that leads to the production of a single isomer as a direct result of the mechanism of the reaction and the stereochemistry of the starting material. E2
- therefore careful choice of the diastereoisomer to be utilised in the reaction will allow specific entry to either the E or the Z alkene

A Stereoselective reaction gives rise to one predominant product because the reaction pathway has a choice. E1 ( E/Z isomers formed , E isomer favoured)

Question 26

which factors influence which reaction (E1/E2) mechanism occurs?

Answer 26

1) the nature of the carbenium ion that could form via an E1 reaction- ( all the factors that affected carbocation stability as listed for SN1 reactions)
2) the nature of the solvent- a good ionising, ion solvating medium will favour E1 reactions but will have little effect on E2 reactions.
3) use of a strong base, or a high concentration of base, will enhance E2 reactions.

-steric effects of the substrate have a less profound effect on elimination reactions, as the base attacks H and not C

Question 27

Discuss elimination versus substitution reactions

Answer 27

1) more basic nucleophiles effect elimination - strong bases attack protons rather than carbon atoms, and this leads to elimination rather than substitution
2) the size of the nucleophile can influence the course of the reaction- to attack a carbon atom, the nucleophile must squeeze past the substituents. Therefore bulky groups on the substrate and use of a bulky base can encourage elimination reactions to occur rather than nucleophilic displacement reactions.
- steric crowding in the substrate also favours elimination reactions over substitution reaction.
3) elimination reactions can be favoured by performing the reaction at high temperatures. In an elimination reaction two molecules become 3 , in a substitution reaction, two molecules become two new molecules. Thus the entropy change in the two reactions will be different .
- ∆G = ∆H - T∆S A reaction in which ∆s is positive is more exothermic at higher temperatures. This is a dominant factor for elimination less for substitution.