Download Electrophilic Addition to Carbonyl Groups – HX

Electrophilic Addition to Carbonyl Groups – HX
Electrophilic Addition to CO
O
H3C
C
H
CH3
Br
OH
OH
H3C
C
Br
OH
H3C
C
Br
H3C
CH3
CH3
H3C
CH3
Br
A halohydrin.
Br
OH
Br
C
C
CH3
H
H3C
O
C
CH3
Electrophilic Addition to Carbonyl Groups – H2O
H
O
H3C
OH2
OH
C
CH3
HO
H
H3C
OH
C
H
Formalin
C
H2O
OH
-H+
H3C
C
CH3
OH
A gem diol
CH3
HO
H
OH
C
CCl3
Chloral Hydrate
Electrophilic Addition to Carbonyl Groups – HOR
Addition-Substitution
Reactions
of Aldehydes and Ketones —
Acetals
& Hemiacetals
Acetals and Ketals
O
H
C
H3CO
CH3
+ 2 HOCH3
H
OCH3
C
+ H2O
CH3
An Acetal
H
O
H
C
H
CH3
OCH3
OH
H
C
HOCH3
CH3
OH
-H+
H
C
CH3
OCH3
Hemiacetal
Electrophilic Addition to Carbonyl Groups – HOR
Acetals & Hemiacetals
H
O
H3C
C
H
CH3
OCH3
OH
H3C
C
HOCH3
OH
-H+
C
H3C
CH3
CH3
OCH3
Hemiacetal
CH2OH
O
CHO
OH
H
CHO
H
HO
H
H
OH
H OH
H
OH
OH
CH2OH
HO
HO
H
H OH
OH
H
H H
OH
O
H O
HO
HO
H
H
H
OH
OH
Conversion of a Hemiacetal into an Acetal
H
O
H
H
C
H
CH3
O
H
O
C
O
CH3
H
H
CH3
H
CH3
CH3
H
H
O
CH3
O
C
O
H
CH3
CH3
H
CH3
O
H
CH3
C
CH(OCH3)2
CH3
O
CH3
C
O
O
For the reverse process...
H3C
H
CH3
O
C
H
CH3
CH3
H+, H2O
H3C
CHO
+ 2 CH3OH
Electrophilic
to Carbonyl
While these
various speciesAddition
are unstable with
respect to the Groups
aldehyde or ketone...
THEY ARE IMPORTANT INTERMEDIATES IN MANY REACTIONS.
Ph
CHBr2
H2O
OH
Ph
O
CH
Ph
Br
+ HBr
C
H
OH
H3C
C
CH2
OCH3
H3O+
H3C
C
O
CH3
OCH3
H3C
C
CH3
+ H2O
 While many of these species are unstable with respect to the aldehyde or ketone,
they are still important intermediates in many reactions!
Acetal Protecting Groups
Using
Acetals to “Protect” Carbonyl Functionalities
Acetals can be used to protect aldehydes and ketones, alcohols and vicinal diols. They
are stable to strong base and strong nucleophiles (Grignards and alkyllithiums) and are
easily removed by aqueous acid.
O
C
O
Mg, Et2O
H
CO2
C
H+
Br
H
CO2H
CH3OH, H+
H3CO
OCH3
C
H+
H3CO
OCH3
C
H
H
H3CO
OCH3
C
CO2
H
Mg, Et2O
Br
MgBr
CO2
 Acetals can be used to protect carbonyl groups (aldehydes, ketones, etc.) They are
stable in the presence of strong bases and nucleophiles and the carbonyl can be
reformed by addition of aqueous acid.
How to Protect a Functional Group
1) “Protect” the group (carbonyl in this case) by
converting it into a less reactive species.
2) Do the desired transformation (on another part of
the molecule) that would have been incompatible with
the unprotected functional group.
3) Remove the “protecting group” to recover the initial
functional group (in this case, addition of aqueous acid
reverts the equilibrium to reactants, regenerating the
ketone)
Acetals from Ketones
Ketones also form acetals, but are sometimes more difficult to prepare:
O
H3C
C
H3CO
CH3
+ 2 HOCH3
O
H3C
TsOH
Toluene
²
C
HO
OH
O
OCH3
C
CH3
+ H2O
O
+ H2O
Acetals as Alcohol Protecting Groups
Cl
PPTS
OH
Cl
O
O
O
Mg,
Diethyl ether
THP (tetrohydropyran) protecting group
PPTS:
ClMg
HO
OH
HClO4,
CH3OH, H2O
HO
O
H
OTHP
NH4Cl,
H2O
O
O
Acetals as Alcohol Protecting Groups
Mechanism:
B
B H
RH2C O
O
H
O
O
O
RH2C O
O
H
B
RH2C O
O
Nucleophilic Addition to Carbonyl Groups
Both C=C and C=O bonds undergo electrophilic addition by the same mechanism..
CH2
H3C
C
H
CH3
O
H3C
C
Br
H
C
H3C
Br
CH3
CH3
CH3
Br
H3C
CH3
H3C
Br
CH3
OH
OH
C
C
Br
H3C
CH3
C
Br
CH3
C=O also undergoes nucleophilic addition whereas C=C does not...
H3C
O
O
CH2
CH2
C
C
C
C
H
H3C
:Nu
Nu
H
H3C
H
H3C
:Nu
Nu
H
Nucleophilic Addition to Carbonyl Groups
•
While carbonyl groups undergo electrophilic addition reactions, the vast
majority of additions to carbonyls are nucleophilic additions.
•
If there is a leaving group attached to the carbonyl group, an electron
pair on the oxoanion will reform the C-O  bond, kicking out the leaving
group.
•
Nucleophilic additions to carbonyl groups are particularly important as
they provide a flexible method for forming new carbon-carbon bonds.
•
If you wanted to make tert-butanol via a nucleophilic addition to
acetone. What nucleophile would you need?
O
O
+
H3C
CH3
?
H3C
OH
H+
CH3
CH3
H3C
CH3
CH3
Nucleophilic Addition to Carbonyl Groups
•
have been
few
examples
of nucleophilic
So...but
far there
we have
seen
very
few examples
of carbon...
nucleophilic carbon
H
N
C
H
R
C
H
C
H
R
C
C
H

C
H

Cl
N
C
C
H

C
H
H

Cl
R
H
NaNH2
H
C
C
C
H
R
C
C
H
+ NH3 + Na+
Nucleophilic Addition to Carbonyl Groups
•François Auguste Victor Grignard (1871-1935) solved this problem
(earning himself a Nobel Prize in 1912) by adding magnesium to organic
compounds containing C-X bonds:
H
+
C
H
H
ether solvent
Mg
C
H
Cl
Cl
Mg
H
H
Br
ether solvent
+
Mg
Mg
Br
•The formation of Grignard reagents is quite general
•Grignard reagents react readily with a variety of electrophiles (but not
alkyl halides).
Nucleophilic Addition to Carbonyl Groups
H
H

C
H

MgCl
H3C
CH3


C O
H3C
H
C
H
H3O+
O-
CH3
H3C
C
H
OH
+MgCl
Nucleophilic Addition to Carbonyl Groups
O
CH3MgI
1) Diethyl ether
O
CH3CH2
C
CH2CH3
CH3CH2
C
2) H+
A 3° alcohol.
O
O
H
1) CH3CH2MgBr,
Et2O
2) H+
Aldehyde
CH2CH3
CH3
Ketone
C
H
C
H
CH2CH3
H
A 2° alcohol.
Nucleophilic Addition to Carbonyl Groups
1) PhMgBr,
Et2O
O
CH2OH
C
H
H
1° carbon, one carbon
larger than the
Grignard.
2) H+
Formaldehyde
Ph
Diethyl
Ether
O
H2C
Mg
CH2
Br
O
H2C
CH2
H+ (aq)
Ph
CH2CH2OH
2-Phenylethanol
Nucleophilic Addition to Carbonyl Groups
With esters...
O
C
OH
1) xs CH3MgBr
2) H+
OCH3
C
CH3
CH3
and with carbon dioxide...
O
MgBr
O
C
2) H+
O
C
OH
Nucleophilic Addition to Carbonyl Groups
Acetylenic Grignards
H3C
C
C
H
O
Diethyl
Ether
+ CH3CH2MgBr
H3C
C
C
MgBr
H
C
+ H3C—CH3
H3C
C
C
CH2O
MgBr
H3O
H3C
C
C
CH2OH
H
Nucleophilic Addition to Carbonyl Groups
Limitations of Grignard Reagents:
•
Grignard reagents cannot be prepared in the presence of hydrogens
that are at all acidic.
•
It is not possible to prepare a Grignard reagent in the presence of any
good electrophile. (The Grignard reagent is always added to the
ketone, aldehyde, ester, nitrile, etc. after it is prepared.)
•
They are incompatible with water, alcohols, amines, amides, carboxylic
acids, thiols and and H–X where X is not = carbon
•
They react with aldehydes, ketones, esters, epoxides, carboxylic acid
derivatives, nitro groups and nitriles.
•
You cannot use/form a Grignard reagent from any molecule that
contains any of the above functionalities.
Nucleophilic Addition to Carbonyl Groups
 Which of the following aromatic bromides can be converted into a
Grignard reagent? Show the products.
Br
Br
Mg, Et2O
Mg, Et2O
HO
Br
Mg, Et2O
CH3O
Br
OHC
Mg, Et2O
Nucleophilic Addition to Carbonyl Groups
 How would you form each of these compounds from a carbonyl
containing compound and a Grignard reagent?
HO
H
HO
OH
Nucleophilic Addition to Carbonyl Groups
Alkyllithium
Alkyllithium
reagents can be prepared by reaction of alkyl halides
Reagents
and
lithium
metal
Prepared
in the
same way, by the reaction of alkyl halides and Lithium metal.
Br
+ 2 Li
Diethyl
Ether
Li
+ LiBr
Phenyllithium
H3CH2CH2CH2C
Br
+ 2 Li
Diethyl
Ether
H3CH2CH2CH2C
n-Butyllithium
Li
Nucleophilic Addition to Carbonyl Groups
 Alkyllithium reagents are like Grignard reagents
but areLike
even
more reactive!
Grignards,
only more so.
C
+
Li
Alkyllithiums are HOT nucleophiles and
extraordinary bases.
² EN = 1.57!
CH3
H3C
C
Li
CH3
 EN of Li = 0.98
 DEN = 1.57!!
t-Butyllithium
It's conjugate acid has
a pKa of 55!! Wow!
Nucleophilic Addition to Carbonyl Groups
 Alkyllithium reagents react like Grignard reagents:
Alkyllithiums react just like Grignards
Br
O
C
Br
H
Diethyl
Ether
Br
H
OH
C
aq. NH4Cl
O
+
O Li
C
PhLi
Li
H
1. Et2O
2. H2O, H +
Nucleophilic Addition to Carbonyl Groups
 Alkynyllithium
reagents
can bereagents
prepared
by prepared
deprotonation
of
Like alkynyl Grignards,
alkynllithium
are also
by deprotonation
of
terminal
alkynes
terminal
alkynes.
Ph
C
C
H
n-BuLi
Ph
C
O
C
C
1)
Br
2) H3O+
OH
H
C
Br
Ph
H
Nucleophilic Addition to Carbonyl Groups: Enolate
and Aldol Reactions
• Enolates are another class of carbon-based nucleophile
• Enolates can be formed by deprotonation of the
hydrogen atom  to a carbonyl group (pKa typically 2025):
O
LDA
C
H3C
CH3
THF
• This generates a nucleophilic carbon atom that can be
used in both SN2 reactions and nucleophilic addition
reactions.
O
C
H3C
CH3
LDA
CH3I
THF
-780C
THF
Nucleophilic Addition to Carbonyl Groups: Enolate
and Aldol Reactions
O
NaOH
C
H3C
CH3
solvent
(water,
alcohol, or
similar)
• Use an excess of a strong base (to form 100%
enolate). This often means using low temperatures
while making the enolate.
• Then add a reactive electrophile (e.g. aldehydes).
O
C
O
LDA
C
H3C
CH3
THF
-780C
H
CH3
THF
• And we’ve extended our carbon chain!
H2O
Nucleophilic Addition to Carbonyl Groups: Enolate
and Aldol Reactions
• This reaction is known as the aldol reaction. It takes
an aldehyde and converts it into an alcohol (while
extending the carbon chain).
• If an aldol reaction is worked up under acidic
conditions, an E2 reaction will follow, giving a double
bond conjugated to the carbonyl group:
O
C
O
LDA
C
CH3
THF
-780C
H
CH3
THF
H+
H2O
Nucleophilic Addition to Carbonyl Groups
 Hydride (H-) Reducing Reagents: The H equivalent of a Grignard Reagent
H
Na+ H B
H
H
_
H
Li+
_
H Al
H
H
LiAlH4 - Lithium Aluminum Hydride or LAH
NaBH4 - Sodium Borohydride
 LAH is a more powerful hydride reducing agent (greater D
² EN). It will
reduce some functional groups that NaBH4 cannot.
Nucleophilic Addition to Carbonyl Groups
 It is convenient (though somewhat simplistic) to think of
this kind of nucleophilic hydrogen as H-, a "hydride".
_
H+
H:
 A bare proton with
 A hydrogen with an electron
no surrounding electrons
pair and a negative charge.
and with a positive charge.
O R
+
C
R
Ketones or
Aldehydes
 The carbon atom of carbonyls
is positively polarized. Hydrides
will attack such species and
hydrogen will add to the carbon atom.
Nucleophilic Addition to Carbonyl Groups
O
C
Br
OH
H
1.) NaBH4, CH3OH
C
2.) NH4Cl (aq)
H
Br
Mechanism:
O
R
_
H:
C
O
R
R
C
H
O
H+
R
R
C
H
H
R
H
Nucleophilic Addition to Carbonyl Groups
 Both LiAlH4 and NaBH4 will easily reduce aldehydes and ketones.
 Hydride reducing agents are advantageous because they are more selective
than catalytic hydrogenation
Alkenes are not reduced because this is a nucleophilic addition
O
H2C
CH
C
CH3
1.) LAH
or NaBH4
2.) H+
HO
H2C
CH
CH CH3
 LiAlH4 will reduce esters and carboxylic acids to alcohols. NaBH4 will not.
LAH will also reduce esters and carboxylic acids to alcohols. Sodium
borohydride will not.
O
C
OCH3
CH(OCH3)2
1.) LAH
2.) H+
CH2OH
CH(OCH3)2
Nucleophilic Addition to Carbonyl Groups
 LAH reduction of carboxylic acids:
O
C
OH
1.) LAH
2.) H+
CH2OH
 This reaction does not occur with Sodium Borohydride.
Nucleophilic Addition to Carbonyl Groups
 The different reactivities of LAH and sodium borohydride allow the
selective reduction of one type of carbonyl (aldehyde/ketone) in the
presence of another (ester/carboxylic acid).
O
O
C
C
OH
1.) NaBH4
2.) H+
H
C
OH
CH2OH
O
 LAH reduces both functional groups:
O
C
C
O
OH
H
1.) LAH
2.) H+
CH2OH
CH2OH
Nucleophilic Addition of N to Carbonyl Groups
 Let's meet the nucleophiles – these can add to carbonyl groups
 Nitrogen nucleophiles can be used to make C=N bonds.
..
N
H
H
H
ammonia
H
H ..
N
..
N
H
H
hydrazine
..
H
..O..
N
..
H
H
hydroxylamine
N
R
H
H
primary amines
 These compounds are v. strong nucleophiles – carbonyl
does not necessarily need to be protonated prior to attack
 pH of 6-7 is required to make a good leaving group
Nucleophilic Addition of N to Carbonyl Groups
O
H3C
C
Bp: 56°
CH3
HO
NH2
"H+"
N
OH
H3C C CH3
An Oxime.
Mp: 59°
+ H2O
 With all of these nucleophiles, the product contains a C=N. Carbon-nitrogen
double bonds are the same strength as carbon-carbon double bonds.
Nucleophilic Addition of N to Carbonyl Groups
 The Mechansim...
H
H B
O
H3C C CH3
O
H3C C CH3
N
HO HH
BH
H
O
H3C C CH3
HO
N
H
B
H
H
O
H3C C CH3
HO
N
H
B
H
O
O
H3C C CH3
N
HO HH
H
H3C
HO
O
C
N
H
H3C C CH3
B
N
HO H
HB
H
H3C
CH3
H
B
HO
C
N
CH3
HB
Nucleophilic Addition of N to Carbonyl Groups
 C=N bonds can be hydrolyzed in the reverse reaction:
H
H
C NH
R
H+
H
NH2
H
O H
H
R
O H
H
H
NH3
R C
R C
C NH2
C
R
R
O
H
H
O
C
NH3
O H
Nucleophilic Addition of N to Carbonyl Groups
 Examples of the products:
O
C
N
H
C
H2NCH2CH2CH3
H
An Imine.
O
NH2
C
N
C
Another Imine.
C
O
CH3CH2CH2
CH2CH2CH3
N
H
H2N NH2
CH3CH2CH2
C
NH2
H
A Hydrazone.
Nucleophilic Addition of N to Carbonyl Groups
 Imines, etc. are important intermediates in the synthesis of amines...
N
R
Ph
LAH, NaBH4
HN
H
R
O
1) CH3CH2CH2NH2
2) H2, Ni
Ph
C
H
CH2
NHCH2CH2CH3
1) H2NOH
2) LAH
3) H+
O
Ph
Ph
H2
C
NH2
Nucleophilic Addition of N to Carbonyl Groups
 Other applications - the syntheses of aldehydes from nitriles.
C N
H
1) DIBAL-H
THF
H
C NH
C O
H+, H2O
2) H2O
 The Beckmann rearrangement of oximes:
O
N
C
HO NH2
H+
C
OH
H+
O
C
O
H
N
N C
(CH2)5
H
n
NYLON 6
Nucleophilic Addition of N to Carbonyl Groups
N
C
OH
N
C
H2O
OH2
N
C
N
OH2
C
O
H
N
C
Nucleophilic Addition of N to Carbonyl Groups
 The Wolff-Kischner reduction:
N
O
HO2C
HO2C
CO2H
NH2
CO2H
H2NNH2, KOH, ²D
HO2C
 General for aliphatic and aromatic ketones
 Aldehydes do not generally reduce cleanly
CO2H