Examples of Naming
O
pentan-2-oneO
OH
2-(1-hydroxyethyl)pentanal
O
O
3-oxopentanal
OO
(E)-3-(but-1-enyl)hexane-2,4-dione
H
CH3
CO2H
CHO
CH3
H
2,3-dimethyl-4-oxobutanoic acid
CHO
benzaldehyde
Boiling pointsFor compounds of comparable molecular weight…
Alkanes, ethers < aldehydes, ketones < alcohols < carboxylic acids
Water SolubilityKetones and Aldehydes, like ethers, can function as hydrogen bond acceptors and smaller compounds have significant water solubility.
Hydrogen BondingDipole-dipoleDispersion Forces
Recall Preparation from AlcoholsOH
CH2OH
HO
Na2Cr2O7
acid, 35 deg.
OH
CO2H
O
Be sure you can balance this kind of reaction.
RCH2OH RCH=OPCC
Use PCC to limit oxidation of primary alcohol to the aldehyde. Secondary are oxidized to ketone.
Can also be done using KMnO4 in base with heat or bleach in acid solution (HOCl).
PCCSecondary
R2CHOH R2C=O
Primary alcohol
Preparations, con’d
• Reaction of acid chloride and Gilman
R Cl
O
R' 2CuLi
R R'
O
R OH
O
SOCl2
R'X
1. Li
2. CuX
RCH2OH
Na2Cr2O7
But where do we get these??
Note that we have two possible disconnects available
RR'
O RHO
O
+ R'X
OHR'
O
+ RX
HOCH2R
R'OH
HOCH2R'
ROH
Example: Prepare 2-butanone from ethyl alcohol
O
CH3CO2H + CH3CH2X
via Gilman andacid chloride
CH3CH2OH
Requirement to start with ethanol suggests a disconnect into two carbon fragments.
Done!
Aldehydes from carboxylic acids
R Cl
O
R OH
O SOCl2 LiAlH(OC(CH3)3)3
R H
O
And from alcohols, as before:
RCH2OH
PCC
RCHO
Reduction
Oxidation
A Common Sequence
RCH2OH
PCC
RCHO
R'OHPX3
RX
MgR'MgX
R R'
OH
Na2Cr2O7
R R'
O
Observe these parts at this moment.
Reactions
Addition of a nucleophile: Nucleophilic Addition
O
Nu: -
O
Nu
O
Nu
tetrahedral intermediate
OH
Nu
OH
Nu
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.
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?).
OH
Nu:
OH
Nu
OH
Nu
O acid
+
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
Addition of Grignard (Trumpets Please)
Recall the formation of a Grignard and its addition to an oxirane
R-XMg
etherR-Mg-X
O
OMgX
R
R-XMg
etherR-Mg-X
O
OMgX
R
OMgX
R
+
OH
R
OH
R
mild acid
Carbonyls may be added to in same way…
If a new chiral center is created both configurations will be produced.
Common Reactions of Grignards
R-Mg-X
acid,weak acid
R-H
H H
O
RCH2OH
primary alcohol
R' H
O
RCHR'
OH
secondary alcohol
O
OH
R
primary alcohol
R' R''
O
RR'R''C-OHtertiary alcohol
R'CO2Etan ester
R2R'COHa tertiary alcohol
Examine reaction with ester further.
CO2
RCO2Hcarboxylic acid
Both of these reactions extend carbon chain & keep -OH functionality at end of chain. Can extend further.
ROHRXRH(D)
ROHRXRCO2H
ROH + R’CH2OHRX + R’CHORCH(OH)R’
ROH + R’R”CHOH
RX + R’R”CO RR’C (OH)R”
ROH + R’CH2OHRX + R’CO2HR2C(OH)R’
Grignard Reacting with an Ester.Look for two kinds of reactions.
R' OEt
OR-Mg-X
R' OEt
O
RR' R
O
R-Mg-X
R' R
OMgX
R
R' R
OH
R
But where does an ester come from?
R'COCl
EtOH
Acid chloride
R'CO2H
SOCl2 Perhaps this carboxylic acid comes from the oxidation of a primary alcohol or reaction of a Grignard with CO2.
Substitution
Addition
Any alcohol will do here.
Synthetic Planning… Use of epoxides and carbonyls offer different disconnect sites.
R-Mg-XO OH
R
Pattern
HO-C-R
New bond. Disconnect
site
Want this to be the nucleophile
(Grignard).
O1. RMgX HO
R
2. H2O, HClepoxide
New bond. Disconnect site.
Pattern
HO-C-C-R
Nucleophile
carbonyl
Patterns to recognize: carbonyl vs oxirane
We can create the following fragments of target molecules by using an organometallic (carbon nucleophile)
O RMgX dil. acid OH
R
reaction with a carbonyl
RMgX dil. acid OH
reaction with a oxirane
O
R
The difference is the extra CH2 when using an oxirane.
Synthetic Planning…
R1
C
R3R2
OHGive synthetic routes to
R1 R2
O
+ R3-Mg-X
R1 R3
O
+ R2-Mg-X
R2 R3
O
+ R1-Mg-X
If none of the Rs are H then these three synthetic routes may be available.
Three different disconnects possible
Example: Synthesize from ethanol
O
OH
CH3CH2X
CH3CH2OH
MgX2
CH3CO2EtOH
CH3CO2H CH3CH2OHCH3CH2OHCH3CH2MgX
O
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.
Done
Bisulfite Addition
O
SOHO
O
O
SHO O
O
OH
SO O
O
Addition product.
Practical importance: liquid carbonyl compounds can be difficult to purify. The bisulfite addition products will be crystalline and may be recrystallized.
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).
Br
Li
Li
O
O
OH
mild acid
bromocyclohexane
Decreased reactivity of electrophile due to steric hindrance to attack. So we used the alkyl lithium instead of a Grignard.
Nucleophiles derived from terminal alkynes
For example, once formed, the new alkynyl alcohol can be hydrated in two ways, Markovnikov and anti Markovnikov.
Carefully observe the structure of the products, the relationship of the OH and the carbonyl.
Note that the regioselectivity used here is only effective if this alkyne is terminal. Otherwise get a mixture.
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.
Addition of hydrogen cyanide
Think of what the mechanism should be….
Followed by protonation of the alkoxide ion (perhaps by unionized HCN).
pH issue. Slightly basic media so that HCN has partially ionized to cyanide ion, the actual nucleophile.
basic
Follow-up reactions on the cyanohydrins…
R CH2R
O NaCN
RCH2R
OH
N
dil acid
acid catalysisdehydration
R
RHC
H2O
N
H2
catalyst RCH2R
OH
NH2
Hydrolysis. Acid, heatorbase, heat
RCH2R
OH
CO2H
We saw this hydrogenation before.
Let’s see what we can do with the mechanism of the hydrolysis of the nitrile group to a carboxylic acid.
The action is at the nitrile group, CN --> CO2H.
But how does a nitrile group behave? What could be happening?
R
N
aq. acid, heat
R
CO2H
+ NH3
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 .
Overall
We are breaking the CN bond; bond order goes from 3 to 0. Probably stepwise.
R
N
R
NH
acid
Again, we are in acid environment. Let’s protonate something…. Protonate the multiple bonded N atom to make better electrophile and attack with the nucleophile, water.
R
NH
HOH
R
NHH2O
R
NHHO
+ H+
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.
R
NH2O
+ H+
Note the bonding pattern here. We have seen it before.
HO NH similar toHO CH2
which tauermerizes in acid or base, keto-enol
HO CH2O
R
NH2HO
OH2
R
NH2HO
OH2
reposition the H+
R
NH3HO
O
H
R
+ NH3
O
HO
Now want to get rid of the NH2. We have all the O’s we need.
We know what we have to do. Have to get the N protonated to make it a good leaving group.
Initial equilibrium with acid
Done.
R
NH2O
R
NH2O
acid
H
HOH
Wittig Reaction
H I PPh3Bu-Li R R
O
R Ror NaH
Example, synthesize CHCH3
or combine them the other way…
Substitution Elimination
Wittig Reaction Mechanism
Ph3P: +
H I
Ph3P
H Acidic hydrogen
Phosphonium ylidePh3P
H
strong base, BuLiPh3P
Nucleophilic center
Ph3P+
R R
O
Ph3P
R
R
O
betaine
Ph3P
R
R
O
oxaphosphetane
Ph3P
R
R
O
oxaphosphetane
Ph3PO
RR
Nucleophilic substitution
Hemiacetals and Acetals, carbonyls and alcohols
(Unstable in Acid; Stable in base)
(Unstable in Acid; Unstable in base)
Addition reaction.
Substitution reaction
Formation of Hemiacetals, catalyzed by either acid or base. Let’s do it in Base first.
hemiacetal
Use Base to set-up good necleophile.
An addition of the alcohol to the carbonyl has taken place. Same mechanism as discussed earlier.
Poor nucleophile Good nucleophile
But first let’s 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.
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.
Hemiacetal to Acetal, Acid Only
Protonate the hemiacetal, setting up leaving group.
Departure of leaving group.
Attack of nucleophile
DeprotonationSubstitution reaction, cf SN1.
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).
Hemiacetal of D-Glucose
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.
The alcoholThe carbonyl
Stabilities of the Anomers…
More stable form, with the OH of the anomeric carbon is equatorial
Less stable form.
Here note the alternating up-down relationships.
Here see the cis relationship of these two OH groups, one must be axial.
Acetals as Protecting Groups
Target molecule
Form this bond by reacting a nucleophile with an electrophile. Choose Nucleophile and Electrophile centers.
E
N
Br-Mg
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??
Grignard would react with this
carbonyl.
Synthetic Problem, do a retrosynthetic analysis
Use Protecting Group for the carbonyl… Acetals are stable (unreactive) in neutral
and basic solutions.Create acetal as protecting group.
Now create Grignard and then react Grignard with the aldehyde to create desired bond.
Remove protecting group.
Same overall steps as when we used silyl ethers: protect, react, deprotect.
protect
react
deprotect
Tetrahydropyranyl ethers (acetals) as protecting groups for alcohols.
Recall that the key step in forming the acetal was creating the carbocation as shown…
Recall that we can create carbocations in several ways:
1. As shown above by a group leaving.
2. By addition of H+ to a C=C double bond as shown next.This cation can now react with an alcohol to yield an acetal. The alcohol becomes part of an acetal and is protected.
This resonance stabilized carbocation then reacts with an alcohol molecule to yield the acetal.
An acid
There are other ways to create carbocations……
Sample Problem
Provide a mechanism for the following conversion
O
HO OHHCl/H2O
O O
OH
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.
O H+ O
H
O
The protonation of the C=CStrongly electrophilic center, now can do addition to the C=O
Now do addition, join the molecules
O
HO OH
O O
HO
O O
OH
Product
Now must open 5 membered ring here. Need to set-up leaving group.
H+
O O
HO
O O
HO
H
Leaving group leaves….
O O
HO
HO O
HO
H
O O
HO
H
Followed by new ring closure.
O O
HO
HO O
HO O
OH OH
Done. Wow!
Sulfur Analogs
Consider formation of acetal O
acetaldehydeethanal
OH OH
dry HCl
OO
Sulfur AnalogO
acetaldehydeethanal
SH SH
dry HCl
SS
dithiane
SS
H
Bu Li
SS
+ BuH
The aldehyde hydrogen has been made acidic
Why acidic?
Sulfur, like phosphorus, has 3d orbitals capable of accepting electrons: violating octet rule.
SS SS
empty sulfur 3d orbital
f illed carbon p orbital
Recall early steps from the Wittig reaction discussed earlier
Ph3P: +
H I
Ph3P
H
Ph3P
H
strong base, BuLiPh3P
This hydrogen is acidic.
Why acidic? The P is positive and can accept charge from the negative carbon into the 3d orbitals
PH
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.
O CNO
CN
electrophile
OSS
O
OH
O
nucleophilic
Can you think of two other examples of Umpolung we have seen?
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.
Note which nitrogen is nucleophilic
H2N
NH
NH2
O
Nucleophilic nitrogen
H2N
NH
NH2
O
Favored by resonance
Less steric hinderance
EnaminesRecall primary amines react with carbonyl compounds to give Schiff bases (imines), RN=CR2.
Primary amine
Secondary AmineSee if you can write the mechanism for the reaction.
But secondary amines react to give enamines
Acidity of Hydrogens hydrogens are weakly acidic
Weaker acid than alcohols but stronger than terminal alkynes.
Learn this table….
Keto-Enol Tautomerism(Note: we saw tautomerism before in the hydration of alkynes.)
Fundamental process
CH3
O
CH2
HO
keto form enol formusually small component
acid or basecatalysis
Mechanism in base:
CH3
O :OH-
CH2
O
Negative carbon, a carbanion, basic, nucleophilic carbon.
CH2
O
Additional resonance form, stabilizing anion, reducing basicity and nucleophilicity.
CH2
HOH-O-H
Protonation to yield enol form.
Details…
Base strengthAlkoxides 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.
O O
H HFor some 1,3 dicarbonyl compounds the enol form may be more stable than the keto form.
More details…
nucleophilicity CH2
O
Nucleophilic carbon
Some examples:O O O Obase
R-X O O
R
CH3
O :OH-
CH2
O
Br-Br
CH2Br
O
Oxidation: Aldehyde CarboxylicRecall from the discussion of alcohols.
Milder oxidizing reagents can also be used
RCHOAg(NH3)2
+
RCO2- + Ag
Tollens Reagent test for aldehydes
“Drastic Oxidation” of Ketones
O
dichromate, etc
at high temperature
CO2H
HO2C
CO2H
HO2C
Obtain four different products in this case.
Mechanism of Wolf-Kishner, C=O CH2
O H2N-NH2N
N
H
H
Recall reaction of primary amine and carbonyl to give Schiff base. Here is the formation of the Schiff base. We expect this to happen.
N
N
H
HN
N H
N
N H
-OH
These hydrogens are weakly acidic,
just as the hydrogens to a
carbonyl are acidic.Weakly acidic hydrogen removed. Resonance occurs. Same as keto/enol tautomerism.
N
N HH-O-H N
N H
H
Protonation (like forming the enol)
N
N H
H
-OH
NN
H
N
N
H
Perform an elimination reaction to form N2.
H-O-HH
H
O
C
C H
O
C
C H
Here is the resonance for the anion from the keto-enol systemO
C
C
H
Haloform Reaction, overall
CH3O
X2
CX3O
NaOH
NaOH
CO2-
+ HCX3
The last step which produces the haloform, HCX3 only occurs if there is an methyl group, a methyl directly attached to the carbonyl.
If done with iodine then the formation of iodoform, HCI3, a bright yellow precipitate, is a test for an methyl group (iodoform test).
CH3
O
methyl
Steps of Haloform ReactionThe first reaction:
CH3O
X2
CX3O
NaOH
CH3O
X2
CH2XO
NaOH
All three H’s replaced byX. 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: C=C + X-X + Br- (alkene acts as nucleophile, ions)Br
Nucleophilic enolate anion: CH3
O :OH-
CH2
O
Br-Br
CH2Br
O
Mechanism of Haloform Reaction-1
C H3
O
R
:OH-
C H2
O
R
Br-Br
CH2Br
O
R
Br-
Repeat twice again to yield C Br3
O
R
Where are we? The halogens have been introduced. First reaction completed.
Using the last of the three possibilities
One H has been replaced by halogen.
But now we need a substitution reaction. We have to replace the CBr3 group with OH.
Mechanism of Haloform - 2
R
CH3O X2
R
CX3O
NaOH
NaOH
R
+ HCX3
OO-
R
CX3O
-OH
R
CX3O
OH
Attack of hydroxide nucleophile. Formation of tetrahedral intermediate. Anticipate the attack…
R
CX3O
OH
Reform the carbonyl double bond. CX3
- is ejected. The halogens stabilize the negative carbon.
R+ -:CX3
OOH
R+ HCX3
OO-
Neutralization.
This is a substitution step; OH- replaces the CX3 and then ionizes to become the carboxylate anion.
Here’s how:
Cannizaro Reaction
Overall:2 RCHO
conc. KOH
heatRCO2
- + RCH2OH
Restriction: no hydrogens in the aldehydes.
H3C
O
CHO
H
CHO
hydrogens No hydrogens
Why the restriction? The hydrogens are acidic leading to ionization.
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 hydrogens).
Nucleophile, attacking carbonyl group.
R
O
H
HO-:
R
O
H
OH
R
OH
R
O
OH
+
R
OH
H
R
O
O
+R
OHH
H
Attack of nucleophilic HO-
Re-establish C=O and eject H- which is immediately received by second RCHO
Acid-base
Experimental Evidence
2 RCDO RD2OH + RCO2-
KOH, H2O
These are the hydrogens introduced by the reaction. They originate in the aldeyde and do not come from the aqueous hydroxide solution.
Kinetic vs Thermodynamic Contol of a Reaction
Examine Addition of HBr to 1,3 butadiene
HBrH
Br
+
Br
H
1,2 product 1,4 product
Mechanism of reaction.
H-Br
HH
Allylic resonance
1,2 product 1,4 product
Br Br
H
BrBr
H
But which is the dominant product?
HBrH
Br
+
Br
H
1,2 product 1,4 product
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?
Thermodynamic Control: Most stable product dominates
Kinetic Control: Product formed fastest dominates
When two or more products may be formed in a reaction A X or A B
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.
HBrH
Br
+
Br
H
1,2 product 1,4 product
Nature of the product mixture depends on the temperature.
Product mixture at -80 deg 80% 20%Product mixture at + 40 deg 20% 80%
Thermodynamic ControlMore stable product
Kinetic Control
Product formed most quickly, lowest Ea
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.
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.
Diels Alder Reaction/Symmetry Controlled Reactions
Quick Review of formation of chemical bond.
HO- + H+ H - O - H
Electron donor
Electron acceptor
Note the overlap of the hybrid (donor) and the s orbital which allows bond formation.
HO- + H+ H - O H
For this arrangement there is no overlap. No donation of electrons; no bond formation.
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.
new bonds
A B
A
B
HOMOdonor
HOMOdonor
LUMOacceptor
LUMOacceptor
B HOMO donates into A LUMO
A HOMO donates into B LUMO Note the
overlap leading to bond formation
Note the overlap leading to bond formation
Try it in another reaction: ethylene + ethylene cyclobutane
new bonds
A B
A B
LUMO
HOMO
LUMO
HOMO
Equal bonding and antibonding interaction, no overlap, no bond formation, no reaction
HO
OEt
using only compoundshaving two carbons as the source of all carbons in the target molecule
Synthesis problem
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