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Organic Chemistry Notes by Jim Maxka
CH 17: Alcohols
Topics:
Naming and properties of alcohols: solubilities and boiling points
Acidity and nature of C-O-H bond
Preparation of alcohols: Rearrangements
Reactions of alcohols
Oxidation/Reduction
Elimination: more rearrangements
Substitutions: SN1/SN2
Protection
Alcohol IR/NMR
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Connections:
OH
2 ways
H3C
H3C
CH3
CH2
OH
H3C
O
OH
H3C
OH
OH
O
R
R
R
R
R
and
R
OR
R
HO
and
OH
R1
R
OH
R1
O
OH
H3C
R
+
R
OR
R1
2 ways
+
R
O
R
R
OH
H 2C
OH
R
CH2
H
O
H
O
O
+
H3C
H3C
CH3
CH3
O
H3C
CH2
OH
H3C
H3C
H
O
H3C
CH3
H3C
CH3
OH
and
CH3
CH3
CH3
OH
CH3
OH
H2C
CH3
H3C
OH
H3C
Br
and
H3C
OH
H3C
Br
CH3
CH17-1
Organic Chemistry Notes by Jim Maxka
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Alcohols: Which is better to drink? HOH or ROH?
A good rule to remember is that simple alcohols is a lot like water. R-OH is a lot like H-OH.
HOH or ROH? That is the question?
Simple alcohols are soluble in water? T F
Simple alcohols have very similar acidity to water? T F
Simple alcohols have similar boiling point as water? T F
Humans have known about alcohol since the beginning of civilization? T F How?
http://www.intox.com/about_alcohol.asp?selectedText=AboutAlcohol
http://www.intox.com/physiology.asp
Naming of alcohols:
Name the following:
OH
OH
OH
H3C OH
HO
HOH2C
OH
OH
OH OH OH
CH2OH
Br
Br
Predict the following physical properties:
Match BP’s:
1000C, 780C, 650C, 1000C, 1170C
Methanol, Ethanol, 1-Butanol, sec-Butyl alcohol, water
Rank solubility in water
1-propanol, 2-propanol, 1-butanol, 1-pentanol, 1-hexanol
Acidity of alcohols:
CH3OH
CH3O- + H+ pKa = 16
Be sure to be able to name alcohol anions!
INDUCTIVE EFFECTS: Identify the EDG and EN(EWG) groups below and notice what happens to acidity
Compare the following reactions:
CF3CH2O-- + H+ pKa = 12
CF3CH2OH
(CH3)3CO- + H+ pKa = 18
(CH3)3COH
RESONANCE EFFECTS: Identify how electron pushing will stabilize the anion of the Conjugate Base:
RO- + H+ pKa = 16 no resonance
ROH
PhO- + H+ pKa = 10 phenoxide is resonance stabilized
PhOH
Draw the 4 resonance structures for phenoxide:
The energy diagram below shows how stabilizing an anion (product) can move the reaction more to the right
Remember that E relates to K, by ∆G = -RTlnK.
RO- + H+
E
106 more acidic
ROH
PhOH
PhO- + H+
rxn
pKa(ROH) – pKa(PhOH) = 6. Keq=106
CH17-2
Organic Chemistry Notes by Jim Maxka
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Write the H+ exchange reaction for Phenol + hydroxide: Predict direction and extent.
Predict the acidity of p-nitrophenol? pKa ~
Predict the acidity of p-methylphenol? pKa ~
Preparation of alcohols
from alkenes
Markovnikov additon
alkene + aqueous acid called hydration. Provide arrows.
H
H2C
H
H2O
+
OH2
O
H
+
H
H2O
O
+
CH3
CH
H3C
H3C
CH3
CH3
+
H
+
OH2
CH3
H3C
Important aspects of this reaction:
(1) Most substituted C+ gets water. Acidic conditions involve C+ like SN1.
(2) One mole of water is consumed.
(3) The acid H+ or H3O+ is a catalyst (not consumed).
Since the reaction involves C+,.watch out for rearrangements. Make sure you understand the following result:
HO
H3C
CH2
H
CH3
H3C
H2O
+
CH3
CH3
Note the #2 carbon is not substituted as expected. The following sequence explains what happened. Draw
arrows.
H
H3C
CH2
CH3
H2O
H
H
H3C
+
CH
H3C
H
+
+
C
H
H2 O
CH3
CH3
What is the driving force for this rearrangement?
What is this rearrangement called?
We will see more of this with the reverse reaction elimination.
In order to control this reaction, we can use mercury reagents. Provide the steps:
2.
Æ
isopropyl alcohol
propene + 1.
Antimarkovnikov addition
propene + 1.
2.
Formation of diols
cyclohexene + 1.
Æ
2.
1-propanol
Æ
cis-1,2-cyclohexanediol
We’ll learn how to make the trans in the next chapter.
CH17-3
Organic Chemistry Notes by Jim Maxka
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Oxidation/Reduction chemistry involving alcohols
Reiew of oxidation/reduction
First some stuff to memorize:
Oxidation means gain of bonds Æ O; Loss of bonds Æ H.
Reduction means gain of bonds Æ H; Loss of bonds Æ O.
CH4 is the most oxidized or reduced organic molecule? What is the oxidation state of C?
What is the most oxidized?
What is the oxidation state of C?
How about the reactions we just reviewed: oxidation or reduction?
Markovnikov addition of water in aqueous acid.
Antimarkovnikov formation of alcohols from hydroboration.
Diol formation:
The one oxidation reaction from before that involves alcohols is the oxidative cleavage of 1,2-diols by
periodic acid HIO4. Cis-1,2-cyclohexanediol under these conditions would go to?
Do you see the oxidation here?
Reductions
We have seen reduction reactions from before did not involve alcohols
propene + ? Æ propane
Why is it called reduction?
Preparation of alchols from reduction of carbonyl compounds:
Here we react C=O with a H:-- (hydride) reagent. The reaction always goes like this:
O
O
H
OH
an alcohol
H
Tetrahedral
H
product
acid workup
H
You need to understand what this workup stuff is all about.
Why must acid be kept away from the hydride reagent?
H:- + H+ Æ
Given that pKa(H2)=38, should hydride be exposed to water or alcohol. Finish the reaction started below and
predict the direction and extent.
RO-H + H:-
There are two reducing reagents used in reduction of carbonyl groups:
Formula Name
Selectivity
types of C=O affected
LiAlH4
Lithium Aluminum Hydride STRONG – NOT
all C=O.
(LAH)
SELECTIVE
NaBH4
Sodium Borohydride
WEAKER -- MORE
aldehydes and ketones, not
SELECTIVE
esters/carboxylic acids
The key to understanding these reagents is that the metals Al and B are related. Both form very stable oxides.
Al-H + C-O Æ C-H + Al-O
Which is more stable C-O or Al-O?
B-H + C-O Æ B-O + C-H
Which is more stable C-O or B-O?
You can reverse the bottom reaction and add the two. The C-H and C-O cancel out.
Al-H + B-O Æ B-H + Al-O
Of the two, Al-O is stronger than B-O. Therefore, Al is more reactive.
CH17-4
Organic Chemistry Notes by Jim Maxka
Provide reagents for the following alcohol syntheses:
OH
O
1. ?
H3C
CH3
2. Aq acid H C
3
O
CH3
1. ?
C
H3C
O
H3C
CH3
CH2
2. Aq acid
Reaction pattern for hydride reagents
C=O
formaldehyde
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+
OH
ethanol
Reaction
O
O
Alcohol
formed
-
H
OH
A
H
H
H
H
aldehyde
H
H
O
O
H
H
H
-
H
OH
A
H
R
R
H
ketone
O
O
H
R
R
R1
ester
O
O
1st mole
R2
OH
A
R1
H
R
R1
H
O
+
R1
O
R1
H
-
A
H
R1 Acid Wrokup
H
H
O
-
OH
H
2nd mole
R2
R1
H
H
O
H
H
H
-
-
O
R1
H
R
R2
H
O
H
H
R1
+
R2
OH
H
CH17-5
Organic Chemistry Notes by Jim Maxka
O
carboxylic acid
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H
H
AlR 3
O
R1
R1
AlR 3
pKa = 5
O
H
O
R1
H
R1
H
O
+
-
O
-
OH
H
A
H
R1 Acid Wrokup
H
R3Al
R1
H
H
3rd mole
H
-
R1
O
+
pKa = 40
O
O
H
O
O
R3Al
2nd mole
R3Al
Type of
alcohol
formed
O
1st mole
H
R1
H
In general, ketones always make 20 alcohols and substituted aldhydes make 10 alcohols.
Practice:
What substitution pattern must be true for the reduction of
formaldhyde?
aldehyde?
carboxylic acid?
keotne?
ester?
Reactions of C=O with Grignards:
A Grignard is a synthon for carbanion (C:-) It is prepared by the reaction of an alkyl halide with Mg metal in
ether.
R-Br + Mg(s) (ether) Æ R-MgBr = R:- + MgBr+
It is important that you understand how a Grignard is formed.
Practice: Starting from benzene, how would you synthesize phenyl grignard?
Starting from propene, how would you synthesize isopropyl grignard?
The Grignard reacts with a carbonyl compound just like the hydride. We must keep acid away from Grignards.
Finish the reaction of CH3CH2-MgBr + H-OH Æ
Predict the direction and extent of the reaction.
A general Grignard reaction away from water is:
O
R-MgBr
O
H
OH
an alcohol
R
Tetrahedral
R
product
acid workup
R
CH17-6
Organic Chemistry Notes by Jim Maxka
Grignard reactions with different C=O stems.
C=O
Formaldehyde
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Reaction
O
O
Type of
alcohol
formed
-
H
OH
A
R
H
H
H
Aldehyde
O
H
R
O
H
R
H
-
H
OH
A
R
R
R
H
Ketone
O
H
R
O
R
R
H
-
H
OH
A
R
R
R
R
Ester
O
O
1st mole
R2
-
R1
O
R
A
R
R1
R
R1
+
R2OH
R
O
O
H
R1
R2O-
OH
H
R1
R
R1
R
-
2nd mole
R
carboxylic acid
+
R
O
R
O
O
R1
R
R
R2
R
O
R
R
R
O
R1
O
+
-
pKa = 5
R
H
pKa = 60
Reactions of Alcohols
Dehydration of alcohols to make alkenes:
Review elimination: What two things must be present for an elimination?
R
LG
R
R
R
H
R
OH
R
H
Bad LG
R
H
R
R
A
+
OH2
R
Good LG
R
H
R
With an alcohol, what is the LG?
What was a leaving group you studied before?
In general, OH- is not a good LG. Why do you think? OH- is a strong
.
To make OH- into a good leaving group, we need to make a weak base. So, the goal is the find the best way
is to make OH- Æ OH2 or an analogue. One way is to add acid.
SN1/E1 indicates acidic conditions. H+ low pH
SN2/E2 indicates basic conditions..Nu;- or hydroxide.
SN1/E1 involves C+, so we get substitution at which position?
Methyl
10
20
30
SN2/E2 involves interaction with a base or nucleophile, so we get substitution at which position?
Methyl
10
20
30
CH17-7
Organic Chemistry Notes by Jim Maxka
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Main Strategy E1 vs E2
E1/SN1 goes through the same intermediate and occurs in acid.
OH
H
H3C
+
+
CH3
OH2
H3C
H
H3C
CH3
CH3
+
C
H3C
S:
H
S
H3C
CH3
CH3
+
CH2
CH2
E2 comes about in basic conditions.
R3
H
Base:
R4
R1
R2
LG
R1
R3
R2
R4
Make sure you understand why E2 is not good for alcohols!
30 alcohols
If the alcohol is 30, then acid (H3O+) is effective enough in making OH- into a good LG. The 30 is stabilized and
the reaction proceeds by E1.
+
OH
H
CH3
H3C
OH2
+
OH2
H
H3C
E1
CH2
H3C
-H
+
CH3
CH3
+
H2O
H3C
Why does this reaction work so well for 30? Draw the intermediate.
CAREFUL!! We need to be on the lookout for
.
Things can get awful crazy here! Explain the following reaction. Draw arrows where necessary.
H2C
CH3
HC
CH3
H3C
CH3 H
HC
CH3
OH
+
OH2
CH3
H3C
CH3
H2C
HC
CH3
H2O
H
CH3
+
+
OH2
C
H3C
CH3
H3C
H2O
C
H
H
CH3
H2C
CH3
C
H3C
major
CH17-8
CH3
Organic Chemistry Notes by Jim Maxka
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20 alcohols
If the alcohol is 20, then acid is not quite reactive enough to make the OH2+ leave, without a lot of heat. Since
heat can burn organics, we use a reagent like POCl3 and pyridine.
What is the role of pyridine? What is the LG here?
O
O
Cl 2P
OH
Cl
O
-
+
P
Cl
O
Cl
P
Cl
O
Cl
Good LG
Cl
+
H
H
H
N
Which E is this mechanism is this one? Would we worry as much about rearrangement.
What is the ultimate fate of the phosphorus reagent?
In general, we use P, S, and Si reagents with C-O because, the formation of the P-O, S-O, and Si-O bond is
more stabilizing than the C-O. That means that there is a thermodynamic driving force for the C-O bond to be
broken.
10 alcohols: To eliminate a 10 alcohol, we really have to heat things up, because generally E2 occurs with
strong base and you can’t have acid and base together. If you heat ethanol up in sulfuric acid, which alkene
would you get?
Why is this dangerous?
Substitution Reactions of Alcohols
30 alcohols: For 30 alcohols, if we mix with strong acid, we will make OH Æ water and create the cation.
The cation can react with the CB of the acid to form SN1 halide or can go through E1 as above.
-
OH
H
Br
H3C
CH3
H3C
H2O
+
OH2
H3C
CH3
+
C
Br
CH2
SN1
CH3
CH3
CH3
H
E1
If there is only alcohol and acid present, elimination is favored because there is only a small concentration of
CB anions to act as nucleophiles in the SN1 reaction.
To force the reaction towards substitution, we add NaBr or whatever anion is the CB of the acid in with the
acid and we get mostly substitution. For 30 alcohols, always an SN1 process:
+
H2O
Br
OH2
OH
H
Br
+
H3C
C
CH3
H C
CH
H C
CH
3
3
3
NaBr
CH3
3
CH3
CH3
If we tried this with 20 and 10 alcohols, we would face 2 main problems: (Remember strong acid present)
CH17-9
Organic Chemistry Notes by Jim Maxka
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For 10 alcohols, the reaction would be too slow with acid, so we use one of two reagents, that push the
reaction through. PBr3 to make R-Br and SOCl2.to make R-Cl (can use PCl5 as well).
In general, we use Al, P, S, and Si reagents with C-O because, the formation of the Al-O P-O, S-O, and Si-O
bond is more stabilizing than the C-O. That means that there is a thermodynamic driving force for the C-O
bond to be broken.
O
O
R
Cl
S
OH
R
O
Cl
+
-
Cl
Cl
-
O
R
S
O
Cl
S
+
Cl
Good LG
H
H
R
Cl
There is another help for this reaction.
O
O
S
O
Cl
-
Cl
+
S (g)
H
HCl
O
The PBr3 reagent works in a similar way as the POCl3 reagent above, but leads to SN2 R-Br.
20 alcohols react with PBr3 and SOCl2 without rearrangement. 20 can react by SN1 also.
Cyclohexanol + PBr3 Æ
A general Procedure for turning –OH into a LG without acid:
Tosylation: There is a way to make OH into such a good LG, it is equivalent to a halide. We react, ROH with
p-tolylsulfonylchloride (p-TosCl) in pyridine (a non-nucleophilic base) to make R-OTos.
Transformation of alcohol to tosylate is shown next.
O
O
R
OH
Cl
CH3
S
R
O
+
-
S
O
O
H
O
Cl
Tol
R
O
+
S
Tol
pyridine
R
OTos
O
H
Good LG
Nu
R
R
Tos
Nu
Tosylates can further be converted to alkyl halides or any other SN2 type reaction with a Nu:.
Why does this reaction work?
What would be the problem if you replaced pyridine with a nucleophilic base?
Oxidation of alcohols
Two reagents: CrO3 in acid (Jones) or basic solution -- strong non-selective or PCC – more selective
CrO3 in acidic medium is usually called Jones reagent. PCC is Pyridinium ChloroChromate.
The fate of oxidizing reagents. Since C gains bonds to O. Cr must lose bonds. Typically, CrO3 Cr(Vl) goes to
Cr(lV) in the form of CrO2.
10 alcohol + PCC Æ aldehyde
O
PCC
H3C
OH
CH2Cl 2
H3C
H
CH17-10
Organic Chemistry Notes by Jim Maxka
10 alcohol + Jones Æ carboxylic acid
O
CrO3-H2SO4
H3C
OH
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H3C
OH
20 alcohol + either Æ ketone
OH
O
CrO3-H2SO4
H3C
CH3
H3C
CH3
30 alcohol + either Æ NR
Concept of Protection of alcohols:
Sometimes, we need to react reagents that are sensitive to the acidity of alcohols. Remember Grignard
reagents are so basic that they can take the H off of alcohols (pKa=16) to the CA of Grignard (pKa=45).
The strategic idea is to replace the H with a placeholder. Perform the reaction and then return the H. This
process is called protection.
(CH3)3SiCl is the reagent of choice. TMS = (CH3)3Si. When the alcohol is protected, replace O-H with OTMS. The idea is that O-TMS like O-Tos does not have an acidic proton that can react. This is similar to the
replacement of the acidic alcohol with the acetyl group that is accomplished in aspirin.
O
OH
O
H3C
O
O
OH
OH
salicylic acid
acetylsalicylic acid
aspirin
wart remover
Theory: Protection works in three phases: (1) protection, (2) reaction and then (3) deprotection. Consider the
following reaction.
O
+
H3C
Me MgBr
+
OH
Protect: TMSCl, base
+
OH
+
Me MgBr
H3C
OTMS
CH3
Deprotect: F- in water
F- is used because Si-F is stronger than Si-O, so TMS lets go.
If MeMgBr reacts directly with the alcohol, you can never get the ketone to react.
CH17-11
Organic Chemistry Notes by Jim Maxka
IR/NMR of alcohols
IR – really broad peak between 3200 and 3500 cm-1.
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CH17-12
Organic Chemistry Notes by Jim Maxka
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Detection of Alcohols
Breathalyzers
Breathalyzers detect alcohol by IR spectroscopy. Which peak do they look for?
This raises many possible defense possibilities:
http://www.drunkdriving-california.net/breathalyzer_tests.html
Mass Spectroscopy
Alcohols tend to split at the C-OH group. Complete these reactions:
CH3CHOHCH3 ffragment Æ
CH3CH2CH2OH fragment Æ
CH17-13
Organic Chemistry Notes by Jim Maxka
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NMR of alcohols 2-5 broad usually not coupled to nearest neighbors. OH is an EN group. Which alcohol are
these, both isomers of C7H8O: Both have IR bands for alcohols.
3H
2H
2H
5H
1H
2H
1H
CH17-14
Organic Chemistry Notes by Jim Maxka
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The following compounds are isomers of C4H10O: Both have IR alcohol bands.
6H
2H
1H
1H
9H
1H
CH17-15