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CH10135 > Carbonyl Organic mechanisms and reactions > Flashcards

Carbonyl Organic mechanisms and reactions Flashcards

1
Q

What does a carbonyl bond consist of?

A

A carbonyl bond (C=O) consists of one strong s-bond and a weaker pi-bond.

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2
Q

How many sites of reactivity do carbonyls have?

A

Three sites of reactivity

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3
Q

What are the three sites of reactivity for a carbonyl?

A

ẟ + carbon - electrophilic C - susceptible to attack from nucleophiles.
ẟ- oxygen - Lewis basic O - reacts with Lewis acids/Bronsted acids.
Acidic α-proton - weakly acidic α-proton - can be deprotonated to form C nucleophile.

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4
Q

What steps does both nucleophilic substitution and addition have?

A
  1. Nucleophilic attack on the carbonyl

2. Protonation of resulting anion or loss of leaving group

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5
Q

Why does the nucleophilic addition happen at the carbonyl carbon?

A

Nucleophiles donate pair of electrons into the π-antibonding orbital of the C=O.
To make a new bond between the carbonyl carbon and the nucleophile, you have to attack the antibonding orbital, and the lowest lying antibonding orbital is the π-antibonding orbital.
The reason they attack the carbonyl carbon is because it has the highest coefficient in the antibonding orbital. And the antibonding orbital, due to electrostatic repulsions, has a slightly shallower angle to the pi-bond.

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6
Q

Why does the nucleophile attack at 107 degrees during nucleophilic addition?

A

Net result, Nucleophile attacks at 107° (Bürgi-Dunitz angle).
The pi orbital is distorted towards the O (the electron density is pulled towards the O) - makes nucleophilic addition difficult because the charge is there it repels the nucleophile - so the antibonding orbital slightly rearranges its geometry to get around this electrostatic repulsion that occurs between the O and the nucleophile.
So instead of the nucleophile coming in at 90° , it actually comes at 107°, either above or below the C.

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7
Q

order these from most to least reactive: acid anhydride, amide, ester, acyl chloride

A

acyl chloride, acid anhydride, ester, amide,

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8
Q

Difference Between Inductive Effect and Resonance Effect?

A

Inductive effect is the effect caused by the induced electrical charges in atoms of a molecule. This charge induction occurs due to the differences in the electronegativity values of atoms.
The resonance effect of a molecule arises when there are double bonds in that molecule.
The main difference between inductive effect and resonance effect is that inductive effect describes the transmission of electrical charges between atoms in a molecule whereas resonance effect describes the transmission of electron pairs between atoms in a molecule.

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9
Q

How are carbonyls like aromatics are affected by resonance and inductive effects?

A

lone pairs on molecules, can donate into the pi system, which reduces the electropositivity at the carbonyl carbon atom, therefore making it less reactive.
So for acyl chlorides, the Cl pulls a lot out for its bond but it doesn’t put much back in from its lone pairs.
But for an amide molecule with the NH2 group, since N is less electronegative, it doesn’t pull as much out from the bond but it drops a lot back in from its lone pair, making the carbonyl carbon more electron rich.

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10
Q

Why are carboxylic acids not included in the carbonyl reactivity series?

A

When treated with a nucleophile, they get deprotonated and form acetate.

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11
Q

Why are aldehydes and ketones different from other carbonyls?

A

They contain alkyl groups on the carbonyl.

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12
Q

Do aldehydes and ketones undergo substitution at the carbonyl centre, and why?

A

Aldehydes and ketones do not undergo substitution at the carbonyl centre since they both have really poor leaving groups.

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13
Q

What is more reactive: aldehyde or ketone? Why?

A

Aldehyde is more reactive.
Inductive effects of alkyl groups surrounding carbonyl.
The aldehyde only has one alkyl group next to the carbonyl carbon so only one alkyl can donate electron density onto the carbonyl carbon whilst a ketone has 2, 2 alkyl groups is better than 1 so that makes the carbonyl carbon more electropositive.

Aldehydes are less hindered than ketones (a hydrogen atom is smaller than any other organic group).
The carbonyl carbon in aldehydes generally has more partial positive charge than in ketones due to the electron-donating nature of alkyl groups. Aldehydes only have one e- donor group while ketones have two.

Electronically, aldehydes have only one R group to supply electrons toward the partially positive carbonyl carbon, while ketones have two electron‐supplying groups attached to the carbonyl carbon. The greater amount of electrons being supplied to the carbonyl carbon, the less the partial positive charge on this atom and the weaker it will become as a nucleus.

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14
Q

What is acid strength affected by?

A

Acid strength is affected by:
Strength on H-X bond.
Stability of conjugate base (most important for organic acids)

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15
Q

How do Carbonyls fit into acid base equilibrium?

A

Can delocalise the negative charge - form a resonance form and stick it on the O.

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16
Q

Why do carbonyl CHs have a lower pKa?

A

This is why carbonyl CHs have a much lower pKa because they can form a conjugate base.

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17
Q

Oxidation level definition?

A

Oxidation level: refers to the number of heteroatom bonds that are bonded to the atom in question.

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18
Q

What happens when you oxidise a primary alcohol?

A

Primary alcohols can be readily oxidised all the way to carboxylic acids.

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19
Q

What happens when you oxidise a secondary alcohol?

A

Secondary alcohols oxidised to ketones

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20
Q

What are two “Classic Methods’’ to achieve the oxidation of alcohols to carboxylic acids?

A 
Jones Oxidation (Na2Cr2O7 , H2SO4 , H2O) 
Potassium Permanganate (H+ or HO- )
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21
Q

What is the problem with Jones oxidation?

A

The problem with Jones oxidation is that it uses stoichiometric amounts of Cr, so every time you do oxidation for primary alcohols you create2 eq of Cr (III) waste.
Chromium waste is particularly toxic and is hard to dispose of.

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22
Q

Three main types of selectivity?

A

Chemoselectivity
regioselectivity
stereoselectivity

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23
Q

What is Chemoselectivity?.

A

Chemoselectivity: which functional group will react.

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24
Q

What is Regioselectivity?

A

Regioselectivity: where it will react.

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25
Q

What is Stereoselectivity?

A

Stereoselectivity: how it will react.

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26
Q

What is the problem of using Jones or KMnO4 to oxidise a primary alcohol to an aldehyde?

A

Use of either Jones or KMnO4 will oxidise primary alcohols to carboxylic acids.
Problem is water - because you then form a hydrate which can be further oxidised.

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27
Q

What did E.J. Corey develop as an alternative to Jones reagent?

A

E.J. Corey developed an alternative to Jones reagent, since a CrO3 derivative was needed which doesn’t require aqueous conditions.
PCC is soluble in organic solvents..

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28
Q

Issues with PCC?

A

Not particularly green, creates a bi-product of Cr(III)

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29
Q

What is Ley Oxidation, and what does it use?

A

In 1987 S. V. Ley and co-workers introduced tetrapropylammonium perruthenate (TPAP) as a mild oxidation of primary / secondary alcohols to aldehydes or ketones.

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30
Q

What does TPAP utilise?

A

Utilises ruthenium in its +7 oxidation state.

Uses ruthenium as its oxidant

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31
Q

What is the co-oxidant used in Ley oxidation?

A

N-Methylmorpholine oxide (NMO)

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32
Q

Why is Ley oxidation relatively green?

A

Uses sub-stoichiometric amounts - so, for example, if you want to turn one mole of the alcohol to one mole of the aldehyde, you can use 0.1 moles or less of ruthenium, and as its catalyst its not decomposed and can be reused = greener alternative.
NMO allows you to recycle the ruthenium.

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33
Q

What is the Dess Martin Oxidation, and what does it use?

A

In 1983 D.B. Dess and J.C. Martin developed a hypervalent Iodine species soon to be known as the Dess-Martin periodinane (aka Dess Martin Reagent or DMP)

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34
Q

Is the Dess-Martin periodinane (DMP) reagent a mild stoichiometric oxidant?

A

Very mild stoichiometric oxidant.
Will stop at the aldehyde.
Creates stoichiometric amounts of DMP waste.

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35
Q

What is the Swern Oxidation, and what does it use?

A

In 1976 D. Swern described a sulfur based method for the oxidation of primary and secondary alcohols.
Utilises sulfur in its +4 oxidation state.
Multiple derivatives of the method.

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36
Q

Why is the Swern Oxidation done at low temperatures?

A

Done at a low temp, because reaction is fast and exothermic.

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37
Q

What is the Pinnick Oxidation, and what does it use?

A

In 1981 H.W. Pinnick described a mild method to oxidise aldehydes to carboxylic acids.
Sodium Chlorite (NaClO2 ) is the oxidant.
2-Methyl-2-butene is utilised as a radical scavenger.

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38
Q

2 examples of reducing agents?

A

metal hydrides

Lewis acid hydrides

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39
Q

Relationship between reactivity and selectivity in metal hydrides?

A

The more reactive the metal hydride, the less selective it is.

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40
Q

What are metal hydrides? Examples?

A

Metal hydrides are one of the most common reducing reagents you will come across.
Source of “H- ‘’ nucleophile.
Like carbonyl compounds, metal hydrides have different reactivities.
Eg. NaBH4

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41
Q

What are Lewis acid hydrides? Examples?

A

These are charge neutral Lewis Acids.
Only source of “H- ” when they form the Lewis acid-base complex.
Useful for reduction of electron rich carbonyl derivatives - such as ester and amides.

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42
Q

What is a Clemmensen reduction reaction and what does it use?

A

aldehyde/ketone -> alkane

uses: Zn(Hg), Concentrated HCl

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43
Q

What is a Wolff-Kishner reduction reaction and what does it use?

A

aldehyde/ketone -> alkane

N2H4.H2O, KOH, >180 degrees

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44
Q

What is cyanide an example of?

A

a carbon based nucleophile

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45
Q

What are nitriles easily converted into?

A

carboxylic acids

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46
Q

What does hydrolysis utilise?

A

Acid (H2SO4) and water

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47
Q

What are organometallic reagents? Most common type derived?

A

Organometallic reagents are compounds which contains carbon-metal bonds.
Alkyl groups can be added to carbonyls via organometallic reagents.

Li and Mg = most common derived type

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48
Q

How can organometallic reagents create new organometallic reagents?

A

They are very strong nucleophiles, and are very strong bases. pKa of conjugate acid >40.
Therefore can deprotonate acid C-H bonds to form new organometallic reagents.
Particularly Alkynes!

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49
Q

What is a Grignard reagent?

A

A Grignard reagent has a formula RMgX where X is a halogen, and R is an alkyl or aryl (based on a benzene ring) group.
Involves insertion of magnesium into carbon-halogen bond (“Oxidative Insertion”)

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50
Q

What is a Wittig Reaction?

A

In the early 1950’s G. Wittig and co co-workers described the use of phosphonium salts to convert aldehydes / ketones into alkenes.
More commonly known as the Wittig reaction.

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51
Q

What is the key reagent used in the Wittig reagent?

A

Utilises a “phosphorus ylid” as the key reagent. Which is prepared in situ from phosphonium salt.

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52
Q

How is phosphonium salt prepared?

A

Phosphonium salt is easily prepared from alkyl halide and phosphine.

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53
Q

What can substituted alkenes exist as?

A

Substituted alkenes can exist as either E/Z diastereoisomers.

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54
Q

What happens of you get an electron withdrawing group on the ylid?

A

If you have an electron withdrawing group on the phosphorus ylid, then you create what is known as a stabilised phosphorus ylid. If you have the stabilised phosphorus ylid then you get the E-alkene.

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55
Q

Are carboxylic acids a Bronsted acid or base and a Lewis acid or base?

A

Carboxylic Acids are Brønsted Acids and Lewis Bases.

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56
Q

Why are carboxylic acids a Bronsted acid?

A

Is a Bronsted acid due to the acidic proton.
The proton is acidic because when the molecule is being deprotonated and we form the conjugate base (carboxylate), we have a stable anion formed - stable due to negative charge being delocalised over 3 atoms.

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57
Q

Are carboxylic acids a strong or weak acid?

A

Strong acids, due to stability of conjugate base.

Have a really low pKa.

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58
Q

What are three ways of organic synthesis to produce a carboxylic acid?

A
  1. From primary alcohol: Jones Oxidation
  2. From aldehyde: Pinnick Oxidation
  3. From nitrile: Acid hydrolysis
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59
Q

What happens for a carboxylic acid to be converted to an acid chloride?

A

A Key functional group interconversion (FGI).
Replaces poor leaving group (-OH) with (-Cl).
Moves it much higher up the carbonyl reactivity series.

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60
Q

What reagent is used to convert a carboxylic acid to an acid chloride?

A

SOCl2

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61
Q

What happens for an acid chloride to be converted to an acid anhydride?

A

Replaces poor leaving group (-OH) with (-CO2R)

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62
Q

How can you form an acid anhydride from a carboxylic acid?

A

Start with carboxylic acid, then treat it with chlorinate reagents (SOCl2) to form an acid chloride. Then you can react your acid chloride with a carboxylate - carboxylates are nucleophilic due to the oxygen and the delocalisation effects of the negative charge into the pi-system, which makes the lone pairs more nucleophilic.

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63
Q

What happens when you react an acid chloride with organometallic reagents?

A

Acyl Chlorides will react with organometallics to give tertiary alcohols.

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64
Q

What type of reaction will acid anhydrides undergo?

A

hydrolysis

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65
Q

Where are esters electrophilic?

A

at the C=O

66
Q

Do they have an acidic proton? If so what is its pKa?

A

Yes, esters have an acidic a-proton with a pKa ~25

67
Q

Why are they Lewis basic?

A

They’re Lewis basic due to the oxygen lone pair.

68
Q

What do you need to add to an acid chloride to get an ester?

A

an alcohol

69
Q

What are the 2 ways that you can synthesise an ester from a carboxylic acid?

A
  1. Condensation Reaction

2. Steglich Reaction

70
Q

What is a practical implication of the Steglich reaction?

A

Urea is also formed

71
Q

How can you form a carboxylic back form an ester?

A

Ester can be hydrolysed with water back to a Carboxylic Acid.
A Key functional group interconversion (FGI).
Acid or hydroxide promoted.

72
Q

For both acid and base catalysis, what pH is the fastest rate at?

A

For base catalysis - fastest rate is at higher pH.

For acid catalysis - fastest rate at lower pH

73
Q

What are 2 key FGI for ester reduction reactions?

A
  1. Hydrides produce primary alcohols

2. Carbon nucleophiles produce tertiary alcohols

74
Q

On an amide, where is the weakest electrophilic carbon

A

the C=O carbon

75
Q

Does an amide have an acidic alpha-proton? If so what pKa is it?

A

Yes, amides have an acidic a-proton at a pKa ~35.

76
Q

Are amides reactive as electrophiles?

A

Not as much as esters, so they require harsher conditions, either with an acid or hydroxide.

77
Q

What reagents are required to reduce an amide down t an amine?

A

Use of BH3 .THF or BH3 .DMS is the more chemoselective.

Afterwards H+

78
Q

When nucleophiles are added to carbonyls wat shape intermediate do they give?

A

trigonal carbon intermediate

79
Q

Are hydrates and hemi-acetals easy or hard to isolate?

A

Hydrate and Hemi-acetal (in most cases) are difficult to isolate.

80
Q

What is the rate determining step in the formation of hemi-acetals?

A

The rate determining step in this reaction is the nucleophilic attack at the carbonyl carbon.

81
Q

How can you increase the formation of hemi-acetals?

A

rate of formation can be increased by addition of acid or base.

82
Q

How does base catalysis speed up the rate of formation of hemi-acetals?

A

In a reaction using NaOH and EtOH, you speed up the reaction because the base will deprotonate the alcohol (known as a partial deprotonation - since the reaction is an equilibrium and the pKa of the hydroxide and the alcohol is similar, the deprotonation reaction is only partial). So the hydroxide will deprotonate the alcohol from the alkoxide, which is a more nucleophilic molecule so it will react quicker with the aldehyde than ethanol ever would.

83
Q

How can you increase the formation of acetals?

A

Rate of formation increased by acid only.

84
Q

What is an experimental issue with the formation of acetals?

A

Each of the steps are reversible - can be a problem experimentally.

85
Q

How to get around the experimental issues in the formation of acetals?

A

A way to get around this is by using molecular sieves, MgSO4, Dean stark, these conditions are good for removing water from a reaction.
The molecular sieves trap waters in them.
MgSO4 will react with the water and trap it on the Mg surface, forming a new Mg species.
Dean Stark collects the water.

86
Q

What is formed in the Baeyer Viliger Reaction?

A

An ester is formed from a ketone.

87
Q

What functional group does a peracid have?

A

-OOH

88
Q

What is a protection group used for?

A

So we use protection groups to protect/mask one molecule’s inherent reactivity

89
Q

What can cyclic O,O-Acetals be formed from?

A

Cyclic O,O-Acetals can be formed from diols.

90
Q

What is formed by combining a primary amine and an aldehyde or ketone?

A

Imine

91
Q

What is required in the formation of an imine?

A

An acid catalyst

92
Q

What happens to the reaction if a pH of below 4 is being used in the formation of an imine?

A

pH below 4 inhibits attack - will accidently protonate the amine and no longer making it nucleophilic.

93
Q

What happens to the reaction if a pH of above 6 is being used in the formation of an imine?

A

pH above 6 inhibits protonation - not enough acid around to allow protonation and thus water to leave

94
Q

What is formed by combining a secondary amine and an aldehyde or ketone?

A

Use of secondary amine changes equilibrium - the imine, enamine equilibrium will shift to the right, so you will form the emanime

95
Q

Are imines electrophilic and how?

A

The carbonyl carbon of the imine is delta positive, so it is electrophilic and can be easily reacted with nucleophiles.

96
Q

What do enamines react similarly to?

A

Enamines react similarly to enols.

97
Q

What does using an enamine mean for a aldehyde/ketone?

A

So using an emanine is a way of alkylating or adding an electrophile to the alpha position of the aldehyde or ketone going via the enamine.

98
Q

What is the best way of making 2o amines?

A

Reductive amination

99
Q

Why do you have to be careful with your choice of reducing reagent in reductive amination?

A

If your hydride source (reducing agent) is too strong, you’ll end up reducing the carbonyl down to the alcohol before it reacts with the amine.

100
Q

In ketone/enol and imine/enamine equilibrium pairs, which species is detected spectroscopically? Why?

A

the ketone and the imine because the equilibrium is set too far to the left.

101
Q

In 1,3-dicarbonyl compounds where does the equilibrium sit?

A

In 1,3-dicarbonyl compounds keto-enol equilibrium is shifted - equilibrium is more to the right so it sits as the enol form (middle).

102
Q

Why does additional stability occur in 1,3-dicarbonyls occur?

A

The additional carbonyl groups offer additional stability - because you can form hydrogen bonds.
Conjugation - provides stability
a 6-membered ring system is formed from hydrogen bonding.
Enol form is now easily visible spectroscopically.

103
Q

How can we force enol formation?

A

By acid catalysis.
Carbonyl groups have Lewis basic lone pairs which react with the acid - protonating the ketone to form an oxonium species.
The water we have left after protonation, comes back to act as a base with the oxonium species
`

104
Q

Why are enols electron-rich alkenes?

A

Enols are electron-rich alkenes because the lone pair on the oxygen can overlap with the pi-system from the C=C and can add electron density into the pi-system

105
Q

What is acid strength affected by?

A

Acid strength is affected by:
Strength on H-X bond.
Stability of conjugate base (most important for organic acids)

106
Q

How are enols are enolates nucleophilic? How do you know this (in terms of MOs)?

A

Via the alpha carbon.
the carbon has the highest coefficient in the HOMO so therefore the enol is most reactive via the carbon atom in the HOMO.

107
Q

For enolates to be deprotonated what orientation does the molecule need to be?

A

Need to have a 90° relationship between the proton that is going to be deprotonated and the C=O bond.
We’ve got to form a C=C bond from the breaking of a C-H bond, so we must have the C-H bond align with the pi-system to allow overlap to occur and to form the new bond.

108
Q

What can a-deprotonation of unsymmetrical carbonyl compounds lead to?

A

α-deprotonation of an unsymmetrical carbonyl compound can lead to the formation of two possible enolates: “kinetic” enolate and a “thermodynamic” enolate

109
Q

Features of a kinetic enolate?

A 
Less Substituted 
Less Stable 
Prefers strong hindered base 
Prefers low temperature (-78 oC) 
Prefers short reaction times.
110
Q

Features of a thermodynamic enolate?

A 
More Substituted 	
More Stable - due to hyperconjugation
Prefers excess ketone 
Prefers higher temperature (25 oC) 
Prefers long reaction times.
111
Q

What is required to do deprotonation of the least substituted position? (enolates)

A

To do the protonation of the least substituted position, you want to use a strong hindered base.

112
Q

What is meant by a strong base?

A

Strong base = pKa of the conjugate acid of the base must be higher than the proton of the carbonyl that you’re deprotonating.

113
Q

Why is the proton from the acid added at the gamma position in enolisation?

A

The proton from the acid is added at the gamma position, maintaining conjugation in the system and adding the proton on.

114
Q

What happens when you deprotonate a stereogenic centre at the alpha position in enolisation?

A

If you deprotonate a stereogenic centre at the alpha position, when you go back to the ketone, any stereogenicity is completely lost.

115
Q

What is an ambident nucleophile?

A

A species with 2 nucleophilic sites

116
Q

What can you use to direct addition to a specific nucleophilic site in ambident nucleophiles?

A

Your choice of electrophile will determine what site addition occurs at.

117
Q

What is a “softer” electrophile? And where will it react on a molecule?

A

If you use a softer electrophile, something which has big diffuse orbitals, you’ll react via the carbon

118
Q

What is a “harder” electrophile? And where will it react on a molecule?

A

If you use a hard electrophile, something small and highly charged, you can react via the oxygen

119
Q

Why do carbonyls tend to react at the carbon?

A

Oxygen has more of the charge. Therefore harder.

But carbon has greater coefficient in the HOMO. Therefore is the softer site.

120
Q

Where do polar aprotic solvents (DMF) tend to react on a carbonyl?

A

At the oxygen.

121
Q

Where do ethereal solvents (Et2O) promote reactions on a carbonyl?

A

At the carbon.

122
Q

What is the difference in the reaction in using a strong versus weak base in enolate formation?

A

If using a strong base, you’ll do a full deprotonation.
You’ll take your ketone, cool it to -78℃, you’ll add your strong base, you’ll use all the base to fully deprotonate the ketone from the enolate, then add the electrophile.

If using a weak base, you wont have full deprotonation - so we’ll never get to the point where we have all of the ketone converted to the enolate because of the acidity difference between the base and the ketone.

123
Q

What is a weak base?

A

A weak base is where the pKa of the conjugate acid of the weak base is lower than the ketone.

124
Q

When using a weak base in enolate formation, why do we add the base and the electrophile together? Is there any issues with this?

A

We add the base and the electrophile in together - so when the enolate is formed it can be intercepted via the electrophile.
Problem is you have lots of the base left over - multiple alkylation may occur.

125
Q

What is a Claisen condensation reaction?

A

When esters can react with their own enolate - Need to convert to enolate and keep cold.

126
Q

What are α,β-unsaturated carbonyls useful for?

A

α,β-unsaturated carbonyls useful electrophiles for enolate alkylation

127
Q

Relationship between the reactivity if the carbonyl group and the proportion of 1,2-addition that takes place

A

The more reactive the carbonyl group, the higher the proportion of 1,2-addition will take place.

128
Q

What is an Aldol Reaction? What is required for the reaction to occur?

A

A key C-C bond forming reaction between 2 carbonyl species. A new C-C bond is formed from a-carbon to carbonyl carbon.
Requires Enolate/Enol and electrophilic carbonyl species

129
Q

What is required for a species to be a nucleophilic partner in the aldol reaction?

A

To be a nucleophilic partner in the aldol reaction, you just need to have alpha protons on your carbonyl - so can generate an enol or enolate and act as a nucleophile.

130
Q

Why do we use an equilibrium arrow in the first part of the mechanism for an aldol reaction with hydroxide as the base?

A

We’re using an equilibrium arrow in the first part of the mechanism due to the fact that we are using hydroxide as a base, and hydroxide has a conjugate acid which is water.
Water has a pKa of about 15, and the pKa of a ketone is about 25.
Because the pKa of the conjugate acid of our base is lower than the pKa of the ketone, we will never get full deprotonation of the ketone (or aldehyde). So only small amounts of enolates are formed.

131
Q

What occurs in the Claisen Schmidt reaction?

A

The aldol reaction will form a dehydration product, sometimes referred to the Claisen-Schmidt product. The excess base from the last part of the mechanism, can re-react with the aldol product that you formed because the pKa of the alpha proton in the aldol product is similar to the alpha proton in the starting product. This forms an enolate.
As soon as the enolate is formed, it just wants to break down, via an E1cB mechanism.

132
Q

In acid-catalyst aldol reactions, what are you forming as your nucleophile?

A

under acidic conditions forming the enol (not enolate) as your nucleophile.

133
Q

Is the enol or enolate more nucleophilic? What does this mean for the reaction?

A

The enol is less nucleophilic than the corresponding enolate so our electrophile (ketone) will be protonated, as the oxonium, as that is the more reactive electrophilic partner

134
Q

What side reactions can the aldol product do?

A

The aldol product can also do side reactions - like another elimination.
It can pick up a proton, which generates a really good leaving group, in our example it is water. So water will leave via an E1 type mechanism to form a stable secondary carbocation, then another proton is lost, regenerating the catalyst and forming the enone.

135
Q

What’s an issue that can arise in self-condensation reactions?

A

Depending on the product formed, the product can be further deprotonated.

136
Q

What is a cross condensation reaction?

A

performing an aldol reaction between two different carbonyl species.

137
Q

Issues with cross condensation reactions?

A

Problems arise because now we have two ketones with 2 sets of acidic Me groups alpha to the carbonyl, so in theory we can form 2 different types of enolate.
If we have 2 different types of enolates, then each one can react with a different electrophilic partner

138
Q

What 2 conditions must be met for cross condensation reactions to occur?

A

Only one carbonyl must be capable of enolization - So only one of the carbonyl species can have acidic CH3’s adjacent to the carbonyl carbon.
The other partner must be incapable of enolization and more electrophilic than the enolizable partner.

139
Q

What issues arise from forming enol/enolates in the presence of aldehydes and ketones?

A

As seen forming enol/enolates in the presence of aldehydes and ketones has issues particularly for “Cross Condensations”
Multiple possible aldol products
Multiple possible dehydration products (conditions permitting)
By product formation.

140
Q

What are specific enol equivalents?

A

Specific enol equivalents are intermediates that still have the reactivity of enols or enolates, but are stable enough to be prepared in good yield from a carbonyl compound.

141
Q

What are good enol equivalent examples?

A

Good enol equivalents are silyl enol ethers and lithium enolates.

142
Q

How can lithium enolates be formed?

A

Lithium enolates can be prepared by the reaction of LDA with ketone. At a low temperature.

143
Q

What do Lithium Enolates in Aldol Reaction do?

A

Uses strong non-nucleophilic bases to do a formal full deprotonation of the ketone.

144
Q

What is needed to get silyl enol ether to react? And why?

A

Lewis acid

The Lewis acid lowers the LUMO of carbonyl sufficiently for the reaction to take place.

145
Q

What are the 2 ways silyl enol ethers can be made?

A

Silyl enol Ethers can be made to 2 ways, “quench” lithium enolate with Me3SiCl or via weak base in the presence of Me3SiCl

146
Q

What are the similarities between enantiomers and what are the differences between enantiomers?

A

Enantiomers behave the same in terms of Rf, melting point etc.
Only difference between enantiomers is how they rotate in a plane of polarised light.

147
Q

What are the differences between diastereomers?

A

Diastereomers will have different Rf, different melting points, different NMR spectra’s etc.

148
Q

What are intermolecular aldol reactions?

A

intermolecular aldol reactions - meaning it is the reaction of 2 separate molecules coming together.

149
Q

What are intramolecular aldol reactions? Give a generic example of when it can occur..

A

Intramolecular reactions are reactions that occur within a particular molecule.
When a molecule contains two ketones

150
Q

What size ring is preferred? Why?

A

5 or 6 membered rings.
thermodynamically favoured, due to the reduction of torsional strain by having the sp3 carbons all at the preferred bond angles.

151
Q

What is the Robinson annulation?

A

The Robinson annulation is a chemical reaction used in organic chemistry for ring formation. It was discovered by Robert Robinson in 1935 as a method to create a six membered ring by forming three new carbon–carbon bonds

152
Q

What 3 separate mechanisms operate in the Robinson annulation?

A

Michael addition
Intramolecular aldol reaction
Dehydration

153
Q

Issue with the Claisen reaction?

A

You make a product which is more acidic than the thing you start with, because you’ve know got a 1,3-dicarbonyl system

154
Q

What is the intramolecular Claisen reaction known as? What is it useful for?

A

The Intramolecular Claisen reaction is known as a Dieckmann Condensation.
Useful for forming rings.

155
Q

What is the Knoevenagel reaction?

A

The aldol condensation between 1,3-dicarbonyls and aldehydes and ketones is known as the Knoevenagel reaction.

156
Q

What type of base is normally used in the Knoevenagel reaction?

A

Amines

157
Q

What happens throughout the reaction when you want to oxidise a primary alcohol to get a carboxylic acid?

A

Using Jones reagents you first oxide the alcohol to an aldehyde. Then the water turns the aldehyde into an acetal. Then this acetal undergoes the same mechanism as the alcohol using Jones reagents. This results in the formation of the carboxylic acid.

158
Q

What happens in the mechanism for the oxidisation of a primary alcohol using Jones oxidation?

A

Because we are in acidic conditions the Na2Cr2O7 gets turned into CrO3, which is electrophilic at the Cr centre. The O is nucleophilic and attacks the Cr. This breaks one of the Cr=O bonds, and under the acidic conditions, the double bond attacks the proton. This results in a chromate ester. To regenerate the acid, we lose the attached proton from the O. We now need to lose a H at the C centre, so one of the Cr=O bonds takes the H, making a bond between the O and H. This then breaks the C-H bond and the electrons from this bond go to the Cr-O bond and creates a Cr=O double bond. This double bond causes the Cr-O bond to break, resulting in an aldehyde. The aldehyde forms the acetal due to the conditions it is under. Finally the acetal undergoes exactly the same mechanism as above with the CrO3, forming the carboxylic acid at the end.

159
Q

Why does a Jones oxidation manage to oxidise the alcohol all the way to the carboxylic acid, but the Ley oxidation does not?

A

Jones reagents are much harsher than Ley oxidation reagents

160
Q

What happens in the mechanism for the oxidisation of an alcohol using Ley oxidation?

A

The nucleophilic O attacks the electrophilic Ru, which causes a Ru=O bond to break, and gives the O a negative charge. We lose the proton attached to the O to reform the acid. The Ru=O bond takes the proton attached to the C, the making of this bond breaks the C-H bond and the electrons from this bond goes to the C-O bond to create the C=O bond. The formation of the double bond, means the O-Ru bond must break. This results in the aldehyde/ ketone being formed.

CH10135 (7 decks)

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