1
Q
What type of bond makes a carbonyl reactive?
A
It has an electrophilic pi bond
2
Q
Draw a carbonyl
A
3
Q
In which direction is the dipole of a carbonyl facing?
A
It is negative at the oxygen, and positive at the less electronegative adjacent carbon
4
Q
What is the hybridization of the carbon and oxygen that are in the carbonyl pi bond?
A
sp2
5
Q
Which atom in a carbonyl is electrophilic?
A
The positive carbon
6
Q
What are the two types of carbonyl?
A
7
Q
What type of reaction do carbonyls undergo?
A
Addition by nucleophiles
8
Q
What are the types of carbonyl reactions? (6)
A
- C-H bond formation (reduction)
- Acetalization (protection/deprotection)
- imine formation
- C-C bond formation (alkylation)
- C double bond C formation (Wittig olefination)
- Ester formation (Baeyer-Villiger oxidation)
9
Q
What are the two possible nucleophilic additions onto carbonyls? Draw the two
A
Nu-, or Hnu
10
Q
Is an acid a proton donor or acceptor?
A
Proton donor
11
Q
When is a subsequent step needed to neutralize a negative charge on the oxygen atom?
A
With strong charged nucleophiles
12
Q
What are the common reducing agents of carbonyls?
A
Metal hydrides:
1. NaBH4 - sodium borohydride
- LiALH4 -lithium aluminum hydride
13
Q
Why are NaH and KH not reducing agents?
A
They are bases
14
Q
What do aldehydes reduce to?
A
Aldehydes -Primary alcohols
Ketones - Secondary alcohols
15
Q
What happens mechanistically if a carbonyl is reduced only using BH4?
A
The oxygen will attach to the BH3 + to make an alkoxy borohydride, which is a reactive reductant
16
Q
What types of solvents need to be used in a carbonyl reduction? Give the 2 examples
A
Aprotic anhydrous
ET2O
EtoAC
17
Q
Describe and draw the final step of a carbonyl reduction in AlH4-
A
The reaction is completed by the addition of an aqueous acid to kick out the alkoxy borohydride
18
Q
What is carbonyl acetalization? (3 steps)
A
The addition of a molecule of water to a carbonyl to yield a hydrate
Addition of alcohol to the molecule to form a hemiacetal
Reaction of hemiacetal to form acetal
19
Q
Is hemiacetal intramolecular or intermolecular?
A
Intra
20
Q
Why is carbonyl acetalization useful?
A
carbonyl groups can be protected by acetalization so that a reduction will not occur on it, then the group can be unprotected after
21
Q
Why is carbonyl acetalization a convenient strategy?
A
It is easily reversible
22
Q
What is the imine formation reaction?
A
It is the condensation of a carbonyl and an amine and formation of water
23
Q
Show how a imine formation would work differently in acidic (slightly), and basic conditions
A
24
Q
When do imine reactions work the best?
A
Slightly acidic (pH 4-6)
25
Draw the mechanism that occurs if an imine reaction is too acidic
26
What is the purpose of an imination?
to reduce a carbonyl group into an amine (reductive amination)
27
Why are carbonyl aminations used for reverse aminations and not a normal SN2 reaction?
Monoalkylated product will react with the electrophile
28
What can happen undesirably in an SN2 reaction that makes it hard to monoalkylate a primary amine?
The product can react with the electrophile as well to form a dialkylated product
29
What reagents/solvents are used in a Grignard?
Reagents - Organomagnesium (MgO)
Solvents - Et2O and THF
30
What is an ester?
31
Why do grignard reagents use anhydrous solvents?
Grignard reagents are very basic
32
What are the reagents of a Grignard alkylation of a carbonyl?
1) RMgBr, Ot2O
2) H3O+ OR NH4Cl/H2O
33
What is the similar but generally more reactive version of organomagnesium?
organolithium
34
How are organic magnesium prepared?
35
How are organolithium reagents prepared?
36
What type of reagent could be used to make a propargylic alcohol? Draw its formation
Acetylide reagent
37
What is yielded when a cyanide is added to a carbonyl group? Draw the mechanism
A cyanohydrin
38
What is the nature of the cyanohydrin, and how is this dealt with in the lab?
Cyanohydrin reactions are very easily reversible, so quenching it with acid will prevent back reactions
39
What is the Wittig reagent? Draw its formation
40
What is the general structure of a Wittig rxn with a carbonyl group?
41
Draw the mechanism of a Wittig reaction (with the oxophosphatane)
42
What is the reagent of a Baeyer - Villiger reaction?
RCO3H - a peracid/peroxy acid
43
Draw the general reactants and products of a Baeyer-Villiger rxn
44
What is the difference in bond strengths between the Wittig rxn and the Baeyer-Villiger?
Wittig - reaction driven by strong p=O
BV - reaction driven by good LG from weak O-O bond
45
What is the BV preference of its carbon next to the O atom?
More substitution
46
What compounds are synthesized from carboxylic acids? (6)
1. Carboxylic acid
2. Ester
3. Amide
4. Acid chlorine
5. Carboxylic anhydride
6. Imide
47
How are carboxylic acids named?
Aldehydes/ketones - oxo first
Cyclic molecules - carboxylic acid on the back of the name
48
How is an acid halide named?
oic replaced with oyl, and acid replaced with halide name
49
How is a carboxylic anhydride named?
acid replaced with anhydride
50
How is an ester named?
replace oic with oate, and name start with oxygen fragment
51
How is an amide named?
oic replaced with amide, prefix N-N, and names of fragments attached to nitrogen
52
What are the steps of a general carbonyl reaction?
Addition of nucleophile, tetrahedral intermediate, elimination of LG
(addition-elimination reactions)
53
What are the general LGs?
X, OR, OCOR, NR2
54
Draw the reaction energy diagram and the rate determining step of the general carbonyl addition-elimination reaction
55
56
Give the order of carbonyl compounds in terms of reactivity
Acid chloride > Acid anhydride > ester / carboxylic acid > amide > carboxylate
57
What is the rule to see how reactive a carboxylic acid derivative is?
The x group has to be a better leaving group than the nucleophile
58
What process forms a carbanion from a carbonyl? What is the resonance state with a charge called?
deprotonation of the carbonyl makes an enolate
59
Draw the reactivity order of enolates
60
What makes an enolate more reactive?
More electron-electron repulsion
61
When a weak base (like hydroxide) is added to a ketone, what are the properties of the enolate?
A small quantity of enolate is formed, and the reaction is readily reversible with ketone predominant in solution
62
Draw the mechanism of formation of an enolate with a stronger base (LDA)
63
Is the enolate formation using a strong base reversible or irreversible?
Irreversible
64
Draw the respective basic and acidic conditions of enolates and electrophiles
65
What does the reactivity of a carbonyl depend on?
the electron donation properties of the carbon substituent
Weak electron donor means reactive electrophilic centre
strong electron donor means less reactive electrophilic reaction centre
66
Draw the order of reactivity of the carbonyls
67
What makes a reactive leaving group?
If it is a weak base (stable), it is electronegative and does not share electrons with the carbonyl
68
Draw the order of reactivity of leaving groups
69
What are the 4 ways a carboxylic acid can be formed?
1. Oxidation of primary alcohol or aldehydes
2. Addition of carbon nucleophile to CO2 (carboxylation)
3. Hydrolysis of carboxylic acid derivatives
4. Hydrolysis of nitriles
70
Order the speed of different hydrolysis reactions to make carboxylic acids
71
Draw the reagents and products of the two hydrolysis reactions in a neutral environments
72
What is saponification?
Ester hydrolysis under basic conditions
73
Draw the mechanism of saponification
74
Draw the mechanism of nitrile hydrolysis and circle which step is tautomerization
75
What reaction conditions are needed for the hydrolysis of nitriles?
76
Draw the reaction conditions of the reaction of an acid chloride and a charged nucleophilic carbonyl
77
Draw acid chloride
78
What can acid chlorides react with? What happens?
charged nucleophiles - image, neutral nucleophiles - the Cl is replaced with the other molecule
79
What is an anhydride?
80
Draw the reaction of an anhydride with an acid chloride
81
How would an anhydride reaction with alcohol be accelerated? Draw it
An amine can be used as a acyl transfer agent, pyridine is often used
82
How are carboxylic acids converted to acid chlorides?
Using chlorinating agents:
-oxalyl chloride (COCl)2
-thionyl chloride (Cl2O2)
83
Draw thionyl chloride
84
Draw the mechanism of the conversion of a carboxylic acid to an acid chloride
85
What are symmetric anhydrides made from? Draw it
symmetric - acid chloride and acid
86
why are unsymmetric anhydrides not used?
products are not selective
87
What reagent helps make anhydrides that react selectively? Draw the mechanism
Yamaguchi reagent, it makes a very good LG
(reagent is the ring)
88
Draw a Yamaguchi reagent anhydride reacting selectively
89
What structure can only be synthesized directly from carboxylic acid and cannot be converted by acid chlorides or anhydrides? What is this process called?
Esters - Fisher esterification
90
Draw fisher esterification
91
Draw the conversion of esters through transesterification
92
Draw the trend of reactivity of carboxylic acid derivatives being reduced by hydrides
93
What is a hydride?
H and something else
94
Draw the reduction of an ester with LIAlH4
95
Draw the reduction of an amide with LiAlH4
96
What is special about the reactions of organometallics with esters? Draw it
They can form tertiary alcohols in 2 additions
97
What is an enolate?
the resonance of the conjugate base of a carbonyl where the oxygen is negatively charged
98
What makes a hydrogen on an enolate more reactive?
Ability to donate electrons
99
What are the three possible reactions and products of enolates and electrophiles?
100
Which carbon is monohalogenated, and what is the structure of the electrophile?
X-X electrophile, alpha position carbon is monohalogenated
101
Draw a monohalogenation under acidic conditions
102
When would a polyhalogenation occur?
In a basic medium
103
Draw a polyhalogenation
104
What bond is formed by an alkylation?
C-C
105
What influences the reactivity of an alkylating agent and draw the order of reactivity
Sterics
106
Describe the alkylation process and starting electrophile
R - LG, quasi-irreversible formation of an enolate in a strong base + reaction with alkyl halide
107
Draw the mechanism of an enolate formation and alkylation
108
What issue arises in the alkylation of an asymmetric ketone? How is the problem dealt with?
regioselectivity - reactions choose a kinetic or thermodynamic enolate
109
Show what the products of thermodynamic or kinetic alkylations are
I
110
What are the conditions of a kinetic enolate?
Strong sterically hindered base (LDA = pKa 37)
low temperature (no reversibility)
111
Is the thermodynamic or kinetic enolate more stable? Which one is faster growing?
Therm is more stable, but kinetic is faster
112
Draw LDA
113
Draw the reaction coordinate diagrams of the formation of kinetic and thermodynamic enolates
Red is therm, blue is kinetic
114
In a kinetic enolate, which hydrogen is taken off?
The most easily accessible one
115
What are the reaction conditions of a thermodynamic enolate reaction?
Weaker base (Et3N, pKa = 11)
High T
116
Draw the reaction to get an enamine, what are the reactants?
secondary amine with ketone
117
What is the use of an enamine?
It is useful for getting monoalkylated products
118
What is the selectivity of the alkylation of enamines using a ketone?
When it is an unsymmetric ketone, the less substituted enamine is formed
119
Draw the selective product formation of an unsymmetric ketone
120
What is an aldolization?
It is the combination of an enol and a carbonyl
121
Draw the mechanism of an aldol with reagents/conditions
122
Why are the starting products of an Aldolation generally favored? What type of reaction does this favor?
Less sterics means a retro aldolization is favored
123
Draw a retroaldolization
124
How can aldol reactions be forced to go forwards?
upon heating the mixture for dehydration, or acidic conditions to make a good LG
125
Draw the dehydrating aldol condensation
126
Draw the acid aldol condensation
127
how are aldolizations made selective?
Ketone and non-enolizable aldehyde are used
128
Draw 3 examples of non-enolizable aldehydes
129
How are aldolizations made to happen without condensation
?
Done in a strong base, such as LDA
130
Draw aldolization without condensation
131
How are intramolecular aldolization products chosen?
Least strained ring
132
Draw a typical intramolecular aldol condensation
133
What is the second type of condensation that is not aldol condensation?
formation of b - ketoesters from esters
134
Why are alkoxides used as the base when Claisen condensation? What is the ideal alkoxide?
To avoid saponification of ester, it is idea to use the same alkoxide as on the ester
135
Draw a claisen condensation
136
What is a dieckmann condensation? Draw it
It is the intermolecular version of a claisen condensation
137
When are enolates easily formed or hard to form?
Easily formed when weak acidic alpha hydrogens
138
Draw the order of increasing reactivity of enolates
139
What is the role of a 1-3 dicarbonate in an SN2 reaction?
It enables regioselective alkylations in series as they remain good nucleophiles
140
Draw a series of alkylations in 1, 3 dicarbonyl enolates
141
How would one get a b - ketoacid? with drawing
Hydrolysis of a B ketoester, and the acid/base workup
142
What does decarboxylation of a beta ketoacid give us? Draw
Ketones
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