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J. G. Rudick
CHE 322: Organic Chemistry IIA
Spring 2017
Lecture 14 (2/22/17)
Chemoselective Reactions of
Phenols, Aryl/Vinyl Halides, & Aryl Ethers
Chapter 18 in Loudon, M.; Parise, J.
Organic Chemistry, 6th Ed. W. H. Freeman: New York, NY, 2016
Prof. Jon Rudick
Office Hours: CHEM 775
Mondays 1:30–2:30p
Tuesdays 1:30–2:30p
Thursdays 2:30p–3:30p
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J. G. Rudick
Chemoselectivity
Spring 2017
“Chemoselectivity is the preferential reaction of one functional
group over another under the reaction conditions employed.”
–Atkinson, R. S. Stereoselective Synthesis. Wiley: New York, NY, 1995.
1) SN2
HO
OH
O
2) SN2
O
Tetrahedron: Asymmetry 2005, 16, 3802–3806
Br
H3CO
C N
1) SN2
Br
H3CO
2) Heck
Reaction
O
OCH2CH3
Synlett 1997, 1187–1189
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J. G. Rudick
Phenols
Spring 2017
Phenols participate in nucleophilic substitution (SN2) reactions
because phenolates are good nucleophiles
Aryl
O
H +
base
Δ
R
X
polar
aprotic
solvent
Aryl
O
R
Nucleophile
PhS–
N≡C–
MeO–
PhO–
N 3–
Cl–
log k
+0.03
–2.5
–3.6
–4.1
–4.1 –5.5
Decreasing Nucleophilicity
Tables 9.4 & 9.5 in Loudon (pp. 398-399)
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J. G. Rudick
Phenols
Spring 2017
Phenols participate in nucleophilic substitution (SN2) reactions
because phenolates are good nucleophiles
Aryl
O
H +
B
Aryl
O
+ B–H
+ R–X
SN2 Transition State
Aryl
R
δAryl O
H
H
O
R
+ X–
X
δ-
These are examples of the
Williamson etherification reaction
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J. G. Rudick
Phenols
Spring 2017
good
leaving group
Br
OH
NaH
O
O
O
N
H
OH
O
DMF
O
NaH is a strong base
(pKa of H2 is ~36)
O
N
H
74% yield
DMF is a polar
aprotic solvent
J. Antibiot. 2001, 54, 1004–1012
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J. G. Rudick
Clicker Question
Spring 2017
Which site reacts faster (or first) with benzyl bromide?
A. Phenoxide (ArO–)
O
O
O
N
H
Br
O
B. Alkoxide (RCH2O–)
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J. G. Rudick
Phenols
Spring 2017
In nucleophilic substitution (SN2) reactions, weaker bases are used
with phenols than the bases used with aliphatic alcohols
Ph
OH
CH3–I
NaH
Ph
OCH3
THF
81% yield
Ph
OH
O
CH3–O S OCH3
O
K2CO3
acetone
RSC Adv. 2014, 4, 29439–29442
Ph
OCH3
99% yield
Macromolecules 2016, 49, 2502–2510
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J. G. Rudick
Phenols
Spring 2017
In nucleophilic substitution (SN2) reactions, weaker bases are used
with phenols than the bases used with aliphatic alcohols
base
Δ
O
O R
+
R
X
H
R'
R'
polar
aprotic
solvent
base (pKa of conjugate acid)
NaH (~36)
NaOH (~16)
NaOMe (~16)
K2CO3 (~10)
NaOAc (~5)
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Alkyl–OH
✔
✔/✗
✔/✗
✗
✗
Aryl–OH
✔
✔
✔
✔
✗
J. G. Rudick
Clicker Question
Spring 2017
(Pre-lecture Quiz Question)
What is the major product of the reaction below?
Br
K2CO3
HO
OH
O
OH
DMF
97% yield
Ph
HO
O
O
OH
A
B
Ph
O
O
C
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Ph
Ph
J. G. Rudick
Chemoselectivity
Spring 2017
The lower pKa of phenols than aliphatic alcohols makes it possible
to perform chemoselective nucleophilic substitution (SN2) reactions
Br
K2CO3
HO
OH
O
OH
DMF
97% yield
Tetrahedron 2013, 69, 4105–4113
Br
H3CO
OH
OH
K2CO3
H3CO
DMF
O
OH
83% yield
J. Am. Chem. Soc. 2009, 131, 6475–6479
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J. G. Rudick
Clicker Question
Spring 2017
Which will react first with methoxide?
A
MeO– Na+
B
+
Br
Cl
C
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R
I
MeOH
J. G. Rudick
Aryl Halides & Vinyl Halides
Spring 2017
Halogens attached to sp2-hybridized carbons (i.e., C(sp2)–X)
do not participate in nucleophilic substitution reactions
Br
Br
Br
+
O– Na+
O
92% yield
J. Org. Chem. 1989, 54, 817–824
O– Na+
I
+
Br
OCH3
Br
O
I
OCH3
Br
83% yield
J. Org. Chem. 2000, 65, 3085–3089
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J. G. Rudick
Aryl Halides & Vinyl Halides
Spring 2017
Energy required for rehybridization of C(sp2) to C(sp) prevents
nucleophilic substitution (SN2) reactions at C(sp2)–X
Nu–
X
δNu
H
Hybrid atomic
orbital
representation of
the antibonding
C(sp2)–X
molecular orbital
X
δ-
Nu
C(sp)
rehybridized
transition state
C(sp2)–to–C(sp) rehybridization is ~5 kcal/mol higher in energy
than C(sp3)–to–C(sp2) rehybridization
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J. G. Rudick
Aryl Halides & Vinyl Halides
Spring 2017
Energy required for rehybridization of C(sp2) to C(sp) prevents
nucleophilic substitution (SN2) reactions at C(sp2)–X
X
X
Nu
Nu–
“Backside attack” at the aromatic C(sp2)–X
antibonding orbital is sterically unreasonable
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X
J. G. Rudick
Phenols
Spring 2017
Selective cleavage of the C(sp3)–O bond over the C(sp2)–O bond
under strongly acidic conditions
O
CH3
HBr
OH
AcOH
93% yield
J. Am. Chem. Soc. 1949, 71, 1265–1268
O
HBr
O
O
O
H2O
O
O
O
OH
O
O
Benzyl cleaves faster than methyl!
15
69% yield
J. Med. Chem. 2003, 46, 5437–5444
J. G. Rudick
Phenols
Spring 2017
Selective cleavage of the C(sp3)–O bond over the C(sp2)–O bond
under strongly acidic conditions
Aryl
O
+ H
CH3
Aryl
H
O
CH3
+ Br
R
H
Aryl O
X
H
Aryl
H
16
O
H
+ CH3Br
J. G. Rudick
Phenols
Spring 2017
Selective cleavage of the C(sp3)–O bond over the C(sp2)–O bond
under strongly acidic conditions
O
O
HBr
OH
O
AcOH
H2O/Et2O
89% yield
Enantiomer 1999, 4, 363–368
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J. G. Rudick
Clicker Question
Spring 2017
(Pre-lecture Quiz Question)
O
OH
HBr
O
O
AcOH
H2O/Et2O
89% yield
What is the other product of this reaction?
Br
AcO
A
Br
B
C
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D
J. G. Rudick
Phenols
Spring 2017
Selective cleavage of the C(sp3)–O bond over the C(sp2)–O bond
under strongly acidic conditions
Aryl
O
+ H
Aryl
H
O
Aryl
O
H
+
H
A unimolecular elimination (E1)
mechanism
+
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H
J. G. Rudick
Aryl Halides & Vinyl Halides
Spring 2017
Elimination reactions occur in vinyl halides, but not aryl halides
+
B
H
Br
H
tBuO–
Cl
Br
K+
Cl
93% yield
Adv. Synth. Catal. 2015, 357, 3255–3261
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J. G. Rudick
Aryl Halides & Vinyl Halides
Spring 2017
Elimination reactions occur in vinyl halides, but not aryl halides
Cl
Br OEt
H
Cl
Cl
KOH
OEt
Cl
OEt
OEt
88% yield
J. Med. Chem. 1985, 28, 347–358
H
OH
Bu4N+ F–
Br
OH
DMF
Δ
97% yield
J. Org. Chem. 2009, 74, 442–444
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J. G. Rudick
Aryl Halides & Vinyl Halides
Spring 2017
Elimination reactions occur in vinyl halides, but not aryl halides
Br
H
Br
N
Br
N
Chem. Ber. 1961, 94, 1833–1838
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J. G. Rudick
Clicker Question
Br
+
F
Spring 2017
Mg
THF, Δ
Which reactive intermediate could form this product?
A
MgBr
Br
F
MgF
B
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C
J. G. Rudick
Clicker Question
+
diene
dienophile
Spring 2017
THF, Δ
Which mechanism is the plausible explanation for the formation of
benzyne?
Br
A
B
MgF
BrMg
F
benzyne
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J. G. Rudick
Lecture 14 Ended Here
Clicker Question Answers
6. B.
9. A.
11. B.
18. C.
23. C.
24. B.
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Spring 2017
J. G. Rudick
Aryl Halides & Vinyl Halides
Spring 2017
Halogens attached to sp2-hybridized carbons (i.e., C(sp2)–X)
do not participate in nucleophilic substitution reactions
Br
CH3O– Na+ +
Cl
Br
Cl
MeOH
I
OCH3
H3CO
I
90% yield
J. Org. Chem. 2010, 75, 1534–1549
Br
O
O– Na+
Br
Br
THF/C6H6
85% yield
Synth. Commun. 2016, 46, 452–455
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J. G. Rudick
Phenols
Spring 2017
Selective cleavage of the C(sp3)–O bond over the C(sp2)–O bond
under strongly acidic conditions
HBr
Cl
O
O
O
Cl
AcOH
O
O
O
OH
O
78% yield
Benzyl cleaves faster than 2º alkyl!
Bioorg. Med. Chem. 2004, 12, 2419–2439
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J. G. Rudick
Aryl Halides & Vinyl Halides
Spring 2017
Elimination reactions occur in vinyl halides, but not aryl halides
H
OH
Bu4N+ F–
OH
Br
DMF
Δ
97% yield
J. Org. Chem. 2009, 74, 442–444
Br
Cl
H
KOH
MeOH
Cl
99% yield
Tetrahedron Lett. 2001, 42, 3105–3107
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J. G. Rudick
Aryl Halides & Vinyl Halides
Spring 2017
Halogens attached to sp2-hybridized carbons (i.e., C(sp2)–X)
do not participate in nucleophilic substitution reactions
Br
Br
O– Na+
Br
O
THF/C6H6
85% yield
Synth. Commun. 2016, 46, 452–455
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J. G. Rudick
Aryl Halides & Vinyl Halides
Spring 2017
Elimination reactions occur in vinyl halides, but not aryl halides
Br
H
KOH
MeOH
99% yield
Tetrahedron Lett. 2001, 42, 3105–3107
Br
H
Cs2CO3
Bu4NOH
Dioxane/H2O
Δ
50% yield
Tetrahedron 2008, 64, 10250–10257
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