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Very Weak Acid Ionization Constants
ACID
CONJ. BASE
pKa
CH3COCH2COCH3
CH3NO2
H2O
C2H5OH
CH3COCH3
CH3COCH-COCH3
CH2–NO2
C2H5O –
CH3COCH2–
9.0
10.2
15.7
15.9
20
RCCH
RCCH –
25
RCH=CH2
CH3CH3
RCH=CH –
44
50
OH –
CH3CH2 –
Weak Acid Ionization Constants
ACID
CONJ. BASE
HF
HNO2
C9H8O4 (aspirin)
HCO2H (formic)
C6H8O6 (ascorbic)
C6H5CO2H (benzoic)
CH3CO2H (acetic)
HCN
C6H5OH (Phenol)
F–
NO2 –
C9H7O4 –
HCO2 –
C6H7O6 –
C6H5CO2 –
CH3CO2 –
CN –
C6H5O –
Ka
7.1 x 10 –4
4.5 x 10 –4
3.0 x 10 –4
1.7 x 10 –4
8.0 x 10 –5
6.5 x 10 –5
1.8 x 10 –5
4.9 x 10 –10
1.3 x 10 –10
pKa=-logKa
3.1
3.3
3.5
3.8
4.1
4.2
4.7
9.3
9.9
Reactions of alcohols.
a. Reactions as acids, with metals.
ROH + Mo
RO- M+ + H.
M = Na, K, Li, Ca, Al, Mg
ROH reactivity order : CH3OH >1 > 2 > 3
Reactivity of alcohols follows the order of their acidity. The main
purpose of this reaction is formation of strong organic bases alkoxides.
Reactions of alcohols.
b. Reactions as bases. Conversion to alkyl halides.
Mechanism:
SN2
ROH + HX
ROH2+
SN1
RX + OH2
X-
R+ + X-
possible rearrangement
Order of hydrogen halide reactivity :
HI > HBr > HCl
Order of ROH reactivity :
3 > 2 > 1< CH3OH
RX
Reactions of alcohols.
c. With phosphorus trihalides. Conversion to alkyl bromide or
iodide. Note that PI3 is generated in situ.
R-OH
PBr 3
P + I2
R-X
The main intent of this reaction is to convert a bad leaving group (OH, strong
base) into a good leaving group (dibromophosphine oxide, weak base, conjugate
base of strong halophosphorous acid). A preferred method for generating alkyl
halides from alcohols when possible carbocation rearrangement is to be avoided.
Usually, 100% inversion of chiral alcohols results.
Reactions of alcohols.
d. With thionyl chloride. Conversion to alkyl chloride.
GOOD LEAVING GROUP
O
R-OH + Cl
S
O
Cl
R3N:
Cl
S
O
R
O
R
+ R3N+H Cl-
O
POOR LEAVING GROUP
Cl
Cl- +
S
SO2
+
Cl-
RCl
The main purpose of this reaction is to convert the OH group
into a good leaving group (chlorosulfonyl, weak base,
conjugate base of very strong chlorosulfurous acid). Likewise, a
mild, preferred method for generating alkyl halides from
alcohols when possible carbocation rearrangement is to be
avoided. Usually, 100% inversion of chiral alcohols results.
Reactions of alcohols.
e. Dehydration/formation of ethers. Mechanism :
+
E2 or E1
C
C
H
OH
+
HA
C
C
H
OH2+
SN2
ROH or R'OH
C
C
H
OR
or
A-
SN1
ROH or R'OH
C
H
C
+
C
H
OR'
C
C
H
OR
or
possible rearrangement
C
HA
C
C
H
OR'
Ether formation (i.e. substitution on protonated alcohol) is
favored by low (< 180C) temperatures and by the presence of
excess alcohol. Elimination is more effective with 3° substrates.
Ethers. A family of molecules with a general formula : R-O-R
(symmetrical ethers) or R-O-R' (unsymmetrical ethers). Due to the
presence of lone electron pairs on an O atom, this molecules are
modestly polar and can serve as acceptors of H-bond. One use of
ethers as solvents is to stabilize the metal or organic cations, i.e.
diethyl ether (Et2O) used as a solvent in Mg Grignard reaction or
tetrahydrofuran (THF) in Li Grignard reaction.
Preparation of ethers. A preferred small scale method for
preparation of unsymmetrical ethers is Williamson synthesis:
RO- M+ + R'X
R'OR + M+X-
RX reactivity order : CH3 >1 > 2
The choice of placement of alkyl groups (i.e. either on an alkoxide or alkyl halide)
is dictated by the need to avoid elimination. Thus 2 or 3 alkyl groups must be
parts of an alkoxide anion while the 1 group is used in an alkyl halide.
Epoxides. 3-membered, cyclic ethers are known as epoxides.
The simplest epoxide is ethylene oxide or oxirane. They are often
used as the substrates for nucleophilic ring opening .
Preparation of epoxides. a. From alkenes and peroxyacids. The most common
method for epoxide synthesis. Usually, m-CPBA (m-chloroperoxybenzoic acid ) is
used. Note, that the reaction is concerted and therefore stereospecific and
stereoselective.
m-CPBA
O
Ar
Ar
O
H
C
H
C
H3C
O
O
O
O
H
H
H3C
H
CH 3
trans-2-butene
H
CH 3
trans-dimethyloxirane
Preparation of epoxides. b. From halohydrins, catalyzed by alkoxide anions.
Note, that the reaction is concerted and therefore stereospecific and stereoselective.
halohydrin
H
H
O-
OH
CH 3
RO -
CH 3
Br
2S,3S-3-bromo-2-butanol
CH 3
H
H
CH 3
Br
O
CH 3
H
- Br H
CH 3
cis-dimethyloxirane
Reactions of epoxides. a. Nucleophilic ring-opening. Also known as basecatalyzed ring-opening. The reaction proceeds by an SN2-like process and the leasthindered carbon is attacked. Only strong bases such as ammonia, alcoholic OH-,
alkoxides, cyanides or Gringard reagents are effective. The reaction is
stereospecific and diastereoselective.
cis-dimethyl oxirane
O
H
H3C
H
H3C
H
H3C
CH3O -
H
H3C
H3C
H3C
OH
O-
O
H
H
OCH 3
-H+
H
H3C
H3C
H
OCH 3
rac-1-methoxy-2-propanol
Reactions of epoxides. b. Acid-catalyzed ring-opening. This mode of
epoxide ring-opening allows for the use of weaker nucleophiles such as halides,
water or alcohols. Unlike the base-catalyzed ring-opening,
the attack proceeds at the 3°carbon if the nucleophile is not a halide anion. If the
nucleophile is a halide anion, the reaction proceeds at the least-hindered carbon.
The reaction is stereospecific and diastereoselective.
H
O
O
H
H3C
H
CH 3
trans-dimethyloxirane
OH
H3C
+
H
H
H3C
H
H2O
OH
+
CH 3
H
H
CH 3
OH 2+
-H+
H3C
H
H
CH 3
OH
meso-2,3-butanediol
Reactions of alcohols.
f. Formation of esters. 1. Formation of esters of sulfonic
acids (alkyl sulfonates).
O
O
R-OH + R'
S
O
POOR LEAVING GROUP
Cl
R3N:
R'
S
O
R
+ R3N+H Cl-
O
GOOD LEAVING GROUP
The main intent of this reaction is to convert a bad leaving group
(OH, strong base) into good leaving groups (sulfonyl oxides,
weak bases, conjugate bases of very strong sulfonic acids).
Reactions of alcohols.
f. Formation of esters. 2. Formation of esters of carboxylic acids.
Two ways are predominant: acid-catalyzed formation from
carboxylic acids and base-catalyzed formation from carboxylic acid
halides. The latter is a preferred, milder method.
O
R
R
+ R'OH
C
O
+
H
R
+ H 2O
C
OH
OR'
O
O
+ R'OH
C
Cl
R3N:
R
+ R3N+H Cl-
C
OR'
Loss of electrons - OXIDATION
-2
CH2=CH2
-4
CH4
CH3CH3
-3
CH3X
CH3OH
CH3NH2
+1
-1
HC
CH
H3C
O
+2
H3C
H
O
+3
H3C
CH3
Gain of electrons - REDUCTION
O
OH
+4
CO2
Reactions of alcohols
g. Oxidation reactions. Formation of aldehydes and ketones.
Preparative methods I.
Catalytic hydrogenation (reduction) or metal hydride reduction of
carbonyl compounds. These reactions introduce a very important
aspect of the carbonyl group chemistry, a nucleophilic addition to the
carbonyl group. In the examples below, this occurs via a hydride
anion. This anion is supplied via a mixture of hydrogen gas and a
metal catalyst (Pt, Pd, Ni) at high temperatures and pressures or via
salts called metal hydrides. Keep in mind that catalytic hydrogenation
will reduce double bonds, therefore:
Metal hydrides are commonly used. Typically these are either the
sodium borohydride (NaBH4) or lithium aluminum hydride (LiAlH4).
In these salts, a BH4- group or a AlH4- group serve as carriers of the
hydride anion. The mechanism of the reaction involves the
formation of a tetrahedral intermediate, an alkoxide anion.
i. Preparation of 1° alcohols from aldehydes, esters or carboxylic acids.
O
H 3CH 2C
H
1. BH 4-
1. NaBH 4
2. H 2O, H +
CH 3CH 2CH 2OH
O
H3CH 2C
H
O
H
-
nucleophilic attack
on the carbonyl group
H3CH 2C
-
H
H
tetrahedral, alkoxide
anion intermediate
2. H 2O
CH 3CH 2CH 2OH
H+
ii. Preparation of 2° alcohols from ketones.
O
H3CH 2C
CH 3
1. LiAlH4
2. H 2O, H +
CH 3CH 2CHOH CH 3
Preparative methods II.
Reactions involving Grignard reagents.
(CH3)2CHd--Mg+ Br Grignard reagents are used as a source of very basic/nucleophilic
carbon. The carbon in a Grignard reagent, being a part of a very
polar, covalent C-metal bond, carries partial negative charge. The
metals most commonly used are Li or Mg. Various alkyl groups may
be utilized, such as 1°, 2° or 3°; vinyl, phenyl etc. In all cases the
order of alkyl halide reactivity is :
RI > RBr > RCl
i. Preparation of Mg Grignards: Diethyl ether (Et2O) is used in
order to stabilize the Mg cation via unshared (lone-pair) electrons
of oxygen.
RX + Mgo
ether
R
Mg+ X-
ii. Preparation of Li Grignards (commonly referred to as alkyl
lithiums): THF (tetrahydrofuran, a cyclic ether) is used in order to
stabilize the Li atom via unshared (lone-pair) electrons of oxygen.
RX + 2Li o
THF
R-Li + Li + X -
As nucleophiles, Grignard reagents are used to make C-C bonds via nucleophilic
opening of epoxides (3-membered cyclic ethers) or nucleophilic addition to the
carbonyl group. These are versatile, mild reactions and are the preferred way of
alcohol synthesis.
The former proceeds with the formation of the alkoxide anion. The use
of an alkoxide anion as a leaving group is possible due to the significant basisity of
the Grignard reagents and the relief of the ring strain inherent in the 3-membered
epoxide rings. The procedure is used to prepare 1° alcohols, and it extends the
carbon framework by 2 carbons.
O
1. (CH 3)2CH-Mg + Br 2. H 2O, H +
H 3C
(CH 3)2CH
O
H2C CH 2
Mg + Br nucleophilic opening
on the epoxide
H 3C
H
(CH 3)2CHC H2C H2OH
O - Mg 2+ BrH
H H
alkoxide anion intermediate
2. H 2O
H+
(CH 3)2CHC H2C H2OH
+ (H O) - Mg 2+ Br-
The 1° alcohols are also formed from the reaction of 1 mole of a
Grignard reagent and methanal (formaldehyde). In this case, the
carbon framework is extended by 1 carbon.
i. Preparation of 1° alcohols from formaldehyde.
O
H
H
1. CH 3CH 2-Mg + I 2. H 2O, H
O - Mg 2+ I -
O
H
CH 3CH 3CH 2OH
+
H
CH 3CH 2
Mg + I nucleophilic attack
on the carbonyl group
H 3CH 2C
H
H
tetrahedral, alkoxide
anion intermediate
2. H 2O
H+
CH 3CH 2CH 2OH
+ (H O) - Mg 2+ I-
The 2° alcohols are formed from Grignard reagents and aldehydes
with two or more carbons, or formate esters (HCOR). The latter
requires 2 moles of a Grignard reagent.
ii. Preparation of 2° alcohols from aldehydes or formate esters .
O
(H 3C) 2C
H
H
1. CH 3-Mg + Cl 2. H 2O, H
+
(CH 3)2CHCHOH CH 3
3° alcohols are obtained from Grignard reagents and ketones or
esters of carboxylic acids. Again, the latter option requires 2 moles
of a Grignard reagent.
iii. Preparation of 3° alcohols from ketones or esters of carboxylic acids.
O
H 3CH 2C
+
CH 3
O
H3C
1. CH 3-Mg Cl
2. H 2O, H +
-
OH
H3C H2C
H 3C
+
1. (CH 3) 2CH-Mg Br
OCH 2CH 3
2. H 2O, H +
-
CH 3
OH
H3C
(H 3C) 2HC
CH(CH 3) 2