Reactions & Mechanisms In Organic Chemistry: Part 1

Question 1

Why is chirality important in organic synthesis?

Answer 1

It imparts different physical, chemical or biological properties on different enantiomers.

E.g. (S)-thalidomide eases morning sickness, whereas (R)-thalidomide causes birth defects.

Question 2

SIGMA BONDS

Why are C-H and C-C bonds difficult to break in a chemical reaction whilst C-X bonds (where X is a heteroatom) are less so?

Answer 2

C-X bonds are polarised and thus reactive towards nucleophilic attack; C-C/C-H bonds are very strong and less polarised.

Question 3

PI BONDS

Give examples of functional groups with pi-bonds present.

Answer 3

Aldehydes, ketones, carboxylic acids, esters, amides, acid halides (all C=O bonds).
Alkenes and alkynes (double and triple bonds are reactive).

Question 4

What does the level of a functional group refer to?

Answer 4

The number of bonds that a given carbon atom has to elements of greater electronegativity.

i.e. One: alcohol, ether, amine, alkene, etc.
Two: aldehyde, Ketone, hydrate, acetal, alkynes, etc.
Three: carboxylic acid, nitrile, anhydride, etc.
Four: carbonate, carbamate

Question 5

How can carboxylic acids be converted to acid chlorides?

Answer 5

Reaction with SOCl2 (thionyl chloride)

Question 6

What must be considered when looking at molecular interactions (i.e. interactions between MOs of different molecules/atoms)?

Answer 6

• The frontier MOs (i.e. HOMO and LUMO, at the ‘frontier’ of electron occupation) and their relative energy levels
• Electrostatic interactions
• Hardness & softness (size, charge, ability to be polarised) and thus whether interactions are electrostatically or FMO driven
• Orbital coefficients
• Symmetry

Question 7

What is a nucleophile?

Answer 7

Electron pair donors- all molecules with free pair of electrons or at least one pi-bond.

Question 8

What is an electrophile?

Answer 8

Electron pair acceptors- all molecules with a full/partial positive charge or that have an atom that does not have an octet of electrons.

Question 9

In what two mechanistic steps does the nucleophilic addition to the carbonyl group (in aldehydes and ketones) take place in acidic solution?

Answer 9

1. Nucleophilic addition to the carbonyl group (due to electrostatic attraction & largest coefficient of pi* on carbon of carbonyl- strongest interaction with nucelophilic)
2. Protonation of the resulting anion

Question 10

What is the angle of attack at the carbonyl group?

Answer 10

Around 107 degrees (known as Bürgi-Dunitz trajectory).

This enables max overlap with the slightly ‘splayed out’ pi*. This and repulsion of the nucleophile from filled pi-bonding orbitals means the angle is more obtuse that 90 degrees.

Question 11

Why does the hydride ion itself not act as a nucleophile in the reduction of an aldehyde or ketone?

Answer 11

It is so small and has such a high charge density that it only ever reacts as a base.
It’s filled 1s orbital is not well matched to interact with the pi* orbital of a C=O bond but is to interact with the sigma* orbital of a H-X bond.

The best and mildest source of hydride is NaBH4- better match between C=O pi* and B-H sigma bond.

Question 12

What happens to the BH3 formally generated following the loss of hydride?

Answer 12

It is sp2 hybridised and has empty p orbital (accepts e- pair) so quickly reacts with oxyanion that has just been generated or molecule of solvent, producing another tetravalent boron anion. This is able to transfer another hydride to a second carbonyl compound…
Continues until all 4H’s used up, so in principle 1:4 molar ratio of NaBH4 to carbonyl.
In practice, reaction not quite as efficient and mechanism drawn with oxyanion being protonated from solvent.

Question 13

Name two types of organometallic reagents.

Answer 13

Organomagnesium compounds (Grignard Reagents, R-MgBr)
Organolithium compounds (R-Li)

Carbon is more electronegative that magnesium and lithium so these compounds are a good source of carbanions.

Question 14

How are Grignard reagents made?

Answer 14

By reacting alkyl, aryl or vinyl (-CH=CH2) halides with magnesium and Et2O (ether) - Mg insertion.

Question 15

How are organolithium compounds made?

Answer 15

By reacting alkyl, aryl or vinyl halides with lithium- Li-Hal Exchange.

NOTE: 2 equivalents of Li needed to generate 1 equivalent of organolithium and 1 equivalent or LiX salt.

Question 16

How are alkynyl (CC triple bond) organometallic reagents synthesised?

Answer 16

1. Deprotonate the alkyne by reaction with a simple alkyl organolithium/Grignard reagent (this is NOT Li-Hal exchange / Mg Insertion).
2. Deprotonate the alkyne with a strong nitrogen base, such as sodium amide (NaNH2).

Question 17

How do organometallic compounds react with aldehydes and ketones?

Answer 17

They act as nucleophile sin a similar way to borohydride, except transfer their alkyl, etc. group instead of a hydride yo form the tetrahedral oxyanion (which then reacts with water to form an alcohol).

NOTE: curly arrows must be drawn going through C atom to represent flow of electrons when bond breaks.

Question 18

Why must there be two steps in the reaction of organometallic coumpunds with aldehydes/ketones?

Answer 18

Water must be added after all the organometallic has reacted- the two are incompatible. Protic solvents destroy the organometallic by rapidly protonating the carbanion.

Question 19

What is the product when water acts as a nucleophile and reacts with aldehydes or ketones?

Answer 19

A hydrate (1,1-diol)

Significant concentrations of hydrate are usually only formed from aldehydes, due to steric hindrance in the tetrahedral product in the ketone.
Ring strain factors (i.e decreased bond angles are favourable) and electronic effects (i.e increased partial charge on C due to electron withdrawing groups) also play a role in the position of equilibrium/rate of reaction.

Question 20

What is the product when alcohols act as nucleophile and react with aldehydes/ketones?

Answer 20

A Hemiacetal or acetal

• Acetal formed if alcohol is in excess / water is removed from the reaction mixture as it forms (to push position of equilibrium forwards)

Question 21

How does an acid catalyst increase the rate of both hydrate and hemiacetal formation?

Answer 21

Makes the carbonyl group more electrophilic by protonating it

Question 22

How does a base catalyst increase the rate of hydrate and hemiacetal formation?

Answer 22

Makes the nucleophile more nucleophilic by deprotonating it (giving a negative charge)

Question 23

Why can acetal formation only be catalysed by acid?

Answer 23

In order to make the OH group in the hemiacetal into a good leaving group (by protonation).

Question 24

What determines whether the product of a nucleophilic addition reaction to the carbonyl group is tetrahedral or trigonal planar in structure?

Answer 24

The stability of the tetrahedral intermediate.
In turn this is depends on how well the groups attached may act as leaving groups (expelled from the molecule, taking a negative charge with it).

e.g. no sensible leaving group when Grignard reagent is added to a ketone.

Question 25

What makes a good leaving group?

Answer 25

Since leaving groups are generally anions, the anion must be stable.
Consider the anion’s conjugate acid: the most acidic conjugate acid will have the most stable anion and be the best leaving group.
Thus the LOWER the pKa of the conjugate acid, the BETTER the LEAVING GROUP.

Question 26

What is the pKa of HCl?

Answer 26

-7

Question 27

What is the pKa of ethanoic acid?

Answer 27

4.8

Question 28

What is the pKa of NH4+?

Answer 28

9.2

Question 29

What is the pKa of ethanol?

Answer 29

15.9 (this is the limit of good leaving group ability)

Question 30

What is the pKa of benzene?

Answer 30

43

Question 31

What is the pKa of CH4?

Answer 31

48

Question 32

Which major factors determine the stability of an anion (and hence the value of pKaH)?

Answer 32

-Electronegative elements (more electronegative, more stable. E.g. see hydrides of second period)
Delocalisation of negative charge (more resonance forms possible via pi orbitals, the more stable. E.g. see chlorine-based acids)
Strength of the A-H bond (weaker, stronger acid. Charge spread over large anion).

Question 33

Why does RSO2OH (sulphonic acids) form a more stable anion than RCOOH, ROH (alkoxides) and ArOH (phenolic systems)?

Answer 33

The charge is delocalised onto three electronegative oxygen atoms (3 resonance forms), whilst in RCOO- and RO- it is delocalised onto 2 and 1 respectively. In ArO- the charge is delocalised onto the aromatic ring (less electronegative C atoms).

Question 34

In what situations can carbon acids be strong?

Answer 34

If the -ve charge can be delocalised from carbon onto more electronegative elements (e.g. nitromethane and 1,3-diketone).

Question 35

How does the hybridisation state of the carbon from which the proton is lost in an acid affect its pKa? Why?

Answer 35

Acidity increases from sp3 to sp2 to sp (this is the HAO that the anion lone pair is held in).

This is because s orbitals are lower in energy and more stable as they’re closer to the nucleus- the more s character an orbital has, the more stable the electrons in it are.

Question 36

For a nucleophilic addition reaction to the carbonyl group, the nucleophile must be sufficiently strong. What determines its strength?

Answer 36

The higher the pKa of HNu, the better the nucleophile Nu.

Poor leaving group

Question 37

The carbonyl group must also be reactive (partial positive charge on C). What governs this?

Answer 37

Two effects must be considered together:
INDUCTIVE EFFECT (withdrawal of electrons through sigma framework)
CONJUGATIVE EFFECT (delocalisation of X lone pair into pi* of carbonyl, lowers reactivity)

Question 38

What is the most reactive carbonyl?

Answer 38

Acid chloride