Transcript Lecture 9a - University of California, Los Angeles

Protective group chemistry
 The need of protective groups arises from
the low chemoselectivity of many reagents
used in synthetic organic chemistry
 The main problem is that the use of protective groups
usually adds two (or more) steps to the reaction sequence
 This generates additional waste 
 It also decreases atom economy (=atoms used that are
part of the final product versus atoms used in the reaction
sequence) 
 Therefore the need for new reagent arises that only target
one specific functional group
 When performing Grignard reactions, many functional groups
react with the Grignard reagent due to various reasons:
 Some functional groups protonate the Grignard reagent because
they possess hydrogen atoms that are acidic:
-OH (pKa~16-18 (alcohol), pKa~8-12 (phenols)), -NHx (pKa~35),
-C≡CH (pKa~25), -SH (pKa~9-12), -COOH (pKa~3-5)
 Some functional groups react with the reagent because they
contain electrophilic atoms: -CHO, -COR, -CONR2, -COOR,
-C≡N, -NO2, -SO2R, epoxides (ring opening)
 If more than one of these functional groups is present in the
molecule, the groups that are not suppose to react will have
to be protected temporarily because some of these reactions
are irreversible (i.e., C-C bond formation)
 Example 1: Reaction of a ketone in the presence of a phenol
group
 Pathway 1
 Step 1: Acid-base reaction
 Step 2: Nucleophilic attack
 Step 3: Acidic workup
 Pathway 2
 Step 1: Protection of OH-group
 Step 2: Nucleophilic attack
 Step 3: Acidic workup
OMgBr
OMgBr
OH
PhMgBr
OH
H3O+
PhMgBr
-PhH
Ph
O
O
OMgBr
Me 3SiCl/Base
OSiMe3
1. H3O+
PhMgBr
O
OH
OSiMe3
Ph
OMgBr
Ph
OH
 In both reactions, the same final product is obtained but
the first pathway requires two equivalents of the Grignard
reagent due to the initial acid-base reaction
Ph
OH
 Example 2: Reaction of a ketone in the presence of an aldehyde
function
 The problem in this reaction is that aldehydes are generally more
reactive than ketones which means that both groups would react
with the Grignard reagent, albeit with different rates
 The higher reactivity of the aldehyde is exploited in the formation
of the cyclic acetal using 1,3-propanediol
O
O
HOCH2CH2CH2OH
H
H
O
HCl
O
O
O
1. CH3MgBr
H
2. HCl/H 2O
OH
 The acetal does not react with the Grignard reagent
 After the Grignard reaction is performed, the protective group is
removed during the acidic workup which restores the aldehyde
function
 Sodium borohydride (NaBH4) is less reactive and more
chemoselective than lithium aluminum hydride (LiAlH4)
 NaBH4 will only reduce ketones and aldehydes and tolerates
the presence of esters, amides, C≡C, nitro, sulfone, R-X, etc.
 LiAlH4 will reduce all carbonyl functions and a broad
variety of other functional groups as well 
 Example 3: Reduction of an ester in the presence of
a ketone/aldehyde
 The ketone function has to be protected using ethylene
glycol to form a cyclic ketal before the reduction of the
ester function is performed
O
HO-CH2CH2-OH
O
O
1. LiAlH4
O
O
+
[H ]
O
2. H3O+
O
O
OH
O
H3O+
X
O
OH
 The protective group is removed during the acidic workup,
which restores the ketone function
 If the two amino acids, glycine (Gly) and alanine (Ala),
were reacted, four dipeptides (aside of polypetides) would
be possible: Gly-Gly, Gly-Ala, Ala-Gly and Ala-Ala 
 In order to obtain one specific dipeptide i.e., Gly-Ala only,
several protective groups have to be used during the dipeptide
formation
 The amino group in glycine is protected using the Boc-group
 The carboxylic acid group of alanine is protected by a benzyl
group (benzyl ester)
 The protected forms of the amino acids are then reacted to
form one specific dipeptide
 DCC is used to activate the carboxylic acid
 The treatment of the initial product with
 Acid removes the BOC group (CO2, tert.-BuOH)
 Pd-C/H2 removes the benzyl group as toluene
 The resulting dipeptide is Gly-Ala only!