Carbenes, :CH2

1
Carbenes, CH2
Preparation of simple carbenes
1.
carbene
2.
Mechanism of the a elimination.
2
Reactions of Carbenes, CH2 (not for synthesis)
Addition to double bond.
liquid
Insertion into C-H bond
Formation of ylide (later)
3
Simmons Smith Reaction (for synthesis, addition
to alkenes to yield cyclopropanes)
CH2I2 Zn(Cu) ? ICH2ZnI
Carbenoid, properties similar to carbenes.
4
Template for Reactions
Why stereospecific, why from same side as OH
group?
Interaction with metal holds the carbenoid on the
top side.
5
Electronic Structure
Electrons paired, singlet
6
Triplet and Singlet Methylene
Dominant form in solution
Gas phase
Rotation can occur around this bond.
7
Aldehydes and Ketones

• Chapter 16

8
Structure
Aldehydes
Ketone
Carbonyl group
sp2
2-pentanone
pentanal
9
Examples of Naming
10
Resonance
result
11
Extension of resonance
12
Boiling points
For compounds of comparable molecular
weight Alkanes, ethers lt aldehydes, ketones
lt alcohols lt carboxylic acids
Hydrogen Bonding
Dipole-dipole
Dispersion Forces
Water Solubility
Ketones and Aldehydes, like ethers, can function
as hydrogen bond acceptors and smaller compounds
have significant water solubility.
13
Recall Preparation from Alcohols
Can also be done using KMnO4 in base with heat or
bleach in acid solution (HOCl).
Be sure you can balance this kind of reaction.
Use PCC to limit oxidation of primary alcohol to
the aldehyde. Secondary are oxidized to ketone.
Primary alcohol
Secondary
PCC
R2CHOH R2CO
14
Preparations, cond

• Reaction of acid chloride and Gilman

But where do we get these??
15
Note that we have two possible disconnects
available
16
Example Prepare 2-butanone from ethyl alcohol
Requirement to start with ethanol suggests a
disconnect into two carbon fragments.
Done!
17
Aldehydes from carboxylic acids
Reduction
And from alcohols, as before
Oxidation
18
A Common Sequence
Observe these parts at this moment.
19
Reactions
Addition of a nucleophile Nucleophilic Addition
Good nucleophile, usually basic

Attack of nucleophile occurs on both sides of
carbonyl group. Produces both configurations.

Overall H Nu was added to carbonyl group
double bond. Notice that the CO bond order was
reduced from 2 to 1. The addition reduced the
bond order. We will use this idea later.
20
Reaction can also be done in acid environment.
Nucleophiles not expected to be as strong (why?)
but the oxygen may become protonated making the
carbonyl a better electrophile (why?).
Very electronegative, protonated oxygen. Pulls
the pi electrons into itself strongly.
Problem If there is too much acid present the
nucleophile may become protonated, deactivating it
21
Addition of Grignard (Trumpets Please)
Recall the formation of a Grignard and its
addition to an oxirane
Carbonyls may be added to in same way
If a new chiral center is created both
configurations will be produced.
22
Common Reactions of Grignards
ROH?RX?RH(D)
Both of these reactions extend carbon chain
keep -OH functionality at end of chain. Can
extend further.
Examine reaction with ester further.
ROH RCH2OH?RX RCO2H?R2C(OH)R
ROH RRCHOH? RX RRCO? RRC (OH)R
ROH?RX?RCO2H
ROH RCH2OH?RX RCHO?RCH(OH)R
23
Grignard Reacting with an Ester.Look for two
kinds of reactions.
Substitution
Any alcohol will do here.
But where does an ester come from?
Acid chloride
Perhaps this carboxylic acid comes from the
oxidation of a primary alcohol or reaction of a
Grignard with CO2.
Addition
24
Synthetic Planning Use of epoxides and
carbonyls offer different disconnect sites.
Pattern HO-C-C-R
epoxide
Nucleophile
New bond. Disconnect site.
New bond. Disconnect site
Pattern HO-C-R
carbonyl
Want this to be the nucleophile (Grignard).
25
Patterns to recognize carbonyl vs oxirane

• We can create the following fragments of target
  molecules by using an organometallic (carbon
  nucleophile)

The difference is the extra CH2 when using an
oxirane.
26
Synthetic Planning
Three different disconnects possible
Give synthetic routes to
If none of the Rs are H then these three
synthetic routes may be available.
27
Example Synthesize from ethanol
Done

• Preliminary Analysis
• Hmmm, even number of carbons, at least that is
  good ethanol is a two carbon molecule.
• Now the problem is to divide it up into smaller
  fragments.
• Ether linkage is easily constructed. Williamson.
• Two butyl groups attached to the central 2 carbon
  fragment. Grignard ester.

28
Bisulfite Addition
Addition product.
Practical importance liquid carbonyl compounds
can be difficult to purify. The bisulfite
addition products will be crystalline and may be
recrystallized.
29
Addition of Organolithium Compounds to Carbonyls
Generally the reactions are the same as for
Grignards but the lithium compounds are more
reactive (and more difficult to handle).
bromocyclohexane
Decreased reactivity of electrophile due to
steric hindrance to attack. So we used the alkyl
lithium instead of a Grignard.
30
Nucleophiles derived from terminal alkynes
Can do all the reactions of an alkyne and an
alcohol. But remember that we have two acidic
groups the more acidic OH and the less acidic
terminal alkyne. We discussed this problem
earlier.
For example, once formed, the new alkynyl alcohol
can be hydrated in two ways, Markovnikov and anti
Markovnikov.
Note that the regioselectivity used here is only
effective if this alkyne is terminal. Otherwise
get a mixture.
Carefully observe the structure of the products,
the relationship of the OH and the carbonyl.
31
Addition of hydrogen cyanide
basic
Think of what the mechanism should be.
pH issue. Slightly basic media so that HCN has
partially ionized to cyanide ion, the actual
nucleophile.
Followed by protonation of the alkoxide ion
(perhaps by unionized HCN).
32
Follow-up reactions on the cyanohydrins
We saw this hydrogenation before.
33
Lets see what we can do with the mechanism of
the hydrolysis of the nitrile group to a
carboxylic acid.
Overall
The action is at the nitrile group, CN --gt
CO2H. But how does a nitrile group behave? What
could be happening?
We are breaking the CN bond bond order goes from
3 to 0. Probably stepwise.
Chemically speaking the nitrogen of the nitrile
is basic (lone pair) and can be protonated. This
makes it a better electrophile (cf. carbonyl).
Multiple bond can undergo addition (cf. carbonyl)
reducing bond order.
Goal Break the C to N bonding and create C-O
bonds. Considerations neither the electrophile
(RCN) nor the nucleophile (water) is very
reactive. Since we are in acid protonate the CN
group to make it a better electrophile. Then
attack it with the water nucleophile to add
water. This results in reduction of C-N bond
order and creation of C to O bonds .
34
Again, we are in acid environment. Lets
protonate something. Protonate the multiple
bonded N atom to make better electrophile and
attack with the nucleophile, water.
What have done so far? Reduced the CN bond order
from 3 to 2 and added one O to the C. Moving in
the right direction! Want to reduce the CN bond
order to zero and introduce more O on the C.
Keep going! To induce the water to attack again
(adds another O) need to increase the reactivity
of the electrophile. Protonate again!! On the O.
35
Initial equilibrium with acid
Now want to get rid of the NH2. We have all the
Os we need. We know what we have to do. Have
to get the N protonated to make it a good leaving
group.
Done.
36
Wittig Reaction
Substitution Elimination
Example, synthesize
or combine them the other way
37
Wittig Reaction Mechanism
Acidic hydrogen
Nucleophilic substitution
Nucleophilic center
Phosphonium ylide
betaine
38
Friedel Crafts Acylation
And then all the reactions of ketones
39
Formation of Hydrates, carbonyls and water.
Carbonyl side of equilibrium is usually favored.
40
Hemiacetals and Acetals, carbonyls and alcohols
Addition reaction.
(Unstable in Acid Unstable in base)
(Unstable in Acid Stable in base)
Substitution reaction
41
Formation of Hemiacetals, catalyzed by either
acid or base. Lets do it in Base first.
But first lets take stock. We have an addition
reaction. Just mixing a carbonyl and an alcohol
do not cause a reaction. One of them must be made
a better reactant. Carbonyl can be made into a
better electrophile by protonating in
acid. Alcohol can become a better nucleophile in
base by ionization.
Use Base to set-up good necleophile.
Poor nucleophile
Good nucleophile
An addition of the alcohol to the carbonyl has
taken place. Same mechanism as discussed earlier.
hemiacetal
42
Alternatively, hemiacetal formation in Acid
Protonation of carbonyl (making the oxygen more
electronegative)
Attack of the (poor) nucleophile on (good)
electrophile.
Deprotonation
Overall, we have added the alcohol to the
carbonyl.
43
Hemiacetal to Acetal, Acid Only
Protonate the hemiacetal, setting up leaving
group.
Departure of leaving group.
Attack of nucleophile
Substitution reaction, cf SN1.
Deprotonation
44
Equilibria
Generally, the hemiacetals and acetals are only a
minor component of an equilibrium mixture. In
order to favor formation of acetals the carbonyl
compound and alcohol is reacted with acid in the
absence of water. Dry HCl) The acetals or
hemiacetals maybe converted back to the carbonyl
compound by treatment with water and acid. An
exception is when a cyclic hemiacetal can be
formed (5 or 6 membered rings).
45
Hemiacetal of D-Glucose
The alcohol
The carbonyl
Try following the stereochemistry here for
yourself
The hemiacetal can form with two different
configurations at the carbon of the carbonyl
group. The carbon is called the anomeric carbon
and the two configurations are called the two
anomers. The two anomers are interconverted via
the open chain form.
46
Stabilities of the Anomers
Here note the alternating up-down relationships.
More stable b form, with the OH of the anomeric
carbon is equatorial
Less stable a form.
Here see the cis relationship of these two OH
groups, one must be axial.
47
Acetals as Protecting Groups
E
Synthetic Problem, do a retrosynthetic analysis
Target molecule
N
Form this bond by reacting a nucleophile with an
electrophile. Choose Nucleophile and Electrophile
centers.
Grignard would react with this carbonyl.
The nucleophile could take the form of an
organolithium or a Grignard reagent. The
electrophile would be a carbonyl.
Do you see the problem with the approach??
48
Use Protecting Group for the carbonyl Acetals
are stable (unreactive) in neutral and basic
solutions.
Create acetal as protecting group.
protect
Now create Grignard and then react Grignard with
the aldehyde to create desired bond.
react
Remove protecting group.
deprotect
Same overall steps as when we used silyl ethers
protect, react, deprotect.
49
Tetrahydropyranyl ethers (acetals) as protecting
groups for alcohols.
Recall that the key step in forming the acetal
was creating the carbocation as shown
There are other ways to create carbocations
Recall that we can create carbocations in several
ways 1. As shown above by a group
leaving. 2. By addition of H to a CC double
bond as shown next.
This resonance stabilized carbocation then reacts
with an alcohol molecule to yield the acetal.
An acid
This cation can now react with an alcohol to
yield an acetal. The alcohol becomes part of an
acetal and is protected.
50
Sample Problem
Provide a mechanism for the following conversion
First examination have acid present and will
probably protonate Forming an acetal. Keep those
mechanistic steps in mind.
Ok, what to protonate? Several oxygens and the
double bond. Protonation of an alcohol can
set-up a better leaving group. Protonation of a
carbonyl can create a better electrophile. We do
not have a carbonyl but can get a similar species
as before.
51
Strongly electrophilic center, now can do
addition to the CO
The protonation of the CC
Now do addition, join the molecules
Product
Now must open 5 membered ring here. Need to
set-up leaving group.
52
Leaving group leaves.
Followed by new ring closure.
Done. Wow!
53
Sulfur Analogs
Consider formation of acetal
Sulfur Analog
54
The aldehyde hydrogen has been made acidic
Why acidic?
Sulfur, like phosphorus, has 3d orbitals capable
of accepting electrons violating octet rule.
55
Recall early steps from the Wittig reaction
discussed earlier
This hydrogen is acidic.
Why acidic? The P is positive and can accept
charge from the negative carbon into the 3d
orbitals
56
Some Synthetic Applications
57
Umpolung reversed polarity
What we have done in these synthetic schemes is
to reverse the polarity of the carbonyl group
change it from an electrophile into a nucleophile.
electrophile
nucleophilic
Can you think of two other examples of Umpolung
we have seen?
58
Nitrogen Nucleophiles
59
Mechanism of Schiff Base formation
Attack of nucleophile on the carbonyl
Followed by transfer of proton from weak acid to
strong base.
Protonation of OH to establish leaving group.
Leaving group departs, double bond forms.
60
Hydrazine derivatives
61
Note which nitrogen is nucleophilic
Nucleophilic nitrogen
Favored by resonance Less steric hinderance
62
Reductive Amination
Pattern R2CO H2N-R ? ? R2CH-NH-R
63
Enamines
Recall primary amines react with carbonyl
compounds to give Schiff bases (imines), RNCR2.
Primary amine
But secondary amines react to give enamines
See if you can write the mechanism for the
reaction.
Secondary Amine
64
Acidity of a Hydrogens
a hydrogens are weakly acidic
Weaker acid than alcohols but stronger than
terminal alkynes.
Learn this table.
65
Keto-Enol Tautomerism
(Note we saw tautomerism before in the hydration
of alkynes.)
Fundamental process
Mechanism in base
Negative carbon, a carbanion, basic, nucleophilic
carbon.
Additional resonance form, stabilizing anion,
reducing basicity and nucleophilicity.
Protonation to yield enol form.
66
Details
Base strength
Alkoxides will not cause appreciable ionization
of simple carbonyl compounds to enolate. Strong
bases (KH or NaNH2) will cause complete
ionization to enolate.
Double activation (1,3 dicarbonyl compounds) will
be much more acidic.
For some 1,3 dicarbonyl compounds the enol form
may be more stable than the keto form.
67
More details
Nucleophilic carbon
nucleophilicity
Some examples
68
Some reactions related to acidity of a hydrogens
Racemization
Exchange
69
Oxidation Aldehyde ? Carboxylic
Recall from the discussion of alcohols.
Milder oxidizing reagents can also be used
Tollens Reagent test for aldehydes
70
Drastic Oxidation of Ketones
Obtain four different products in this case.
71
Reductions two electron
NaBH4
Or LiAlH4
72
Reductions Four Electron
Clemmenson
Wolf-Kishner
73
Mechanism of Wolf-Kishner, CO ? CH2
Recall reaction of primary amine and carbonyl to
give Schiff base. Here is the formation of the
Schiff base. We expect this to happen.
These hydrogens are weakly acidic, just as the
hydrogens a to a carbonyl are acidic.
Weakly acidic hydrogen removed. Resonance occurs.
Same as keto/enol tautomerism.
Protonation (like forming the enol)
Perform an elimination reaction to form N2.
74
Haloform Reaction, overall
The last step which produces the haloform, HCX3
only occurs if there is an a methyl group, a
methyl directly attached to the carbonyl.
a methyl
If done with iodine then the formation of
iodoform, HCI3, a bright yellow precipitate, is a
test for an a methyl group (iodoform test).
75
Steps of Haloform Reaction
The first reaction

• All three Hs replaced by
• This must happen
• stepwise, like this

Pause for a sec We have had three mechanistic
discussions of how elemental halogen, X2, reacts
with a hydrocarbon to yield a new C-X bond. Do
you recall them?
Radical Reaction R. X-X ? R-X
X. (initiation required)
Addition to double bond CC X-X ?
Br- (alkene acts as nucleophile, ions)
Nucleophilic enolate anion
76
Mechanism of Haloform Reaction-1
Using the last of the three possibilities
One H has been replaced by halogen.
Repeat twice again to yield
Where are we? The halogens have been introduced.
First reaction completed.
But now we need a substitution reaction. We have
to replace the CBr3 group with OH.
77
Mechanism of Haloform - 2
This is a substitution step OH- replaces the CX3
and then ionizes to become the carboxylate anion.
Heres how
Attack of hydroxide nucleophile. Formation of
tetrahedral intermediate. Anticipate the attack
Reform the carbonyl double bond. CX3- is ejected.
The halogens stabilize the negative carbon.
Neutralization.
78
Cannizaro Reaction
Overall
Restriction no a hydrogens in the aldehydes.
a hydrogens
No a hydrogens
Why the restriction? The a hydrogens are acidic
leading to ionization.
79
Mechanism
What can happen? Reactants are the aldehyde and
concentrated hydroxide. Hydroxide ion can act
both as Base, but remember we have no acidic
hydrogens (no a hydrogens). Nucleophile,
attacking carbonyl group.
Attack of nucleophilic HO-
Acid-base
Re-establish CO and eject H- which is
immediately received by second RCHO
80
Experimental Evidence
These are the hydrogens introduced by the
reaction. They originate in the aldeyde and do
not come from the aqueous hydroxide solution.
81
Kinetic vs Thermodynamic Contol of a Reaction
Examine Addition of HBr to 1,3 butadiene
82
Mechanism of reaction.
Allylic resonance
But which is the dominant product?
83
Nature of the product mixture depends on the
temperature.
Product mixture at -80 deg 80
20 Product mixture at 40
deg 20 80
Goal of discussion how can temperature control
the product mixture?
84
When two or more products may be formed in a
reaction A ? X or A ? B
Thermodynamic Control Most stable product
dominates
Kinetic Control Product formed fastest dominates
Thermodynamic control assumes the establishing of
equilibrium conditions and the most stable
product dominates.
Kinetic Control assumes that equilibrium is not
established. Once product is made it no longer
changes.
Equilibrium is more rapidly established at high
temperature. Thermodynamic control should
prevail at high temperature where equilibrium is
established. Kinetic Control may prevail at low
temperature where reverse reactions are very slow.
85
Nature of the product mixture depends on the
temperature.
Product mixture at -80 deg 80
20 Product mixture at 40
deg 20 80
More stable product
Thermodynamic Control
Kinetic Control
Product formed most quickly, lowest Ea
86
Formation of the allylic carbocation.
Can react to yield 1,2 product or 1,4 product.
87
Most of the carbocation reacts to give the 1,2
product because of the smaller Ea leading to the
1,2 product. This is true at all
temperatures. At low temperatures the reverse
reactions do not occur and the product mixture is
determined by the rates of forward reactions. No
equilibrium.
88
Most of the carbocation reacts to give the 1,2
product because of the smaller Ea leading to the
1,2 product. This is true at all
temperatures. At higher temperatures the reverse
reactions occur leading from the 1,2 or 1,4
product to the carbocation. Note that the 1,2
product is more easily converted back to the
carbocation than is the 1,4. Now the 1,4 product
is dominant.
89
Diels Alder Reaction/Symmetry Controlled Reactions
Quick Review of formation of chemical bond.
Electron donor
Electron acceptor
Note the overlap of the hybrid (donor) and the s
orbital which allows bond formation.
For this arrangement there is no overlap. No
donation of electrons no bond formation.
90
Diels Alder Reaction of butadiene and ethylene to
yield cyclohexene.
We will analyze in terms of the pi electrons of
the two systems interacting. The pi electrons
from the highest occupied pi orbital of one
molecule will donate into an lowest energy pi
empty of the other. Works in both directions A
donates into B, B donates into A.
B HOMO donates into A LUMO
Note the overlap leading to bond formation
LUMO acceptor
LUMO acceptor
A HOMO donates into B LUMO
HOMO donor
HOMO donor
Note the overlap leading to bond formation
B
A
91
Try it in another reaction ethylene ethylene
? cyclobutane
LUMO
LUMO
Equal bonding and antibonding interaction, no
overlap, no bond formation, no reaction
HOMO
HOMO
92
Reaction Problem
93
Synthesis problem
94
Mechanism Problem
Give the mechanism for the following reaction.
Show all important resonance structures. Use
curved arrow notation.