baldwin’s rules nadia fleary-roberts 02/05/12. proposed in 1976 by sir jack baldwin guidelines for...
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Baldwin’s Rules
Nadia Fleary-Roberts02/05/12
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•Proposed in 1976 by Sir Jack Baldwin
•Guidelines for ring closing reactions of 3- to 7-membered rings-
•empirical rules derived from experimental observations
J. Chem. Soc. Chem. Commum., 1976, 734-736Advanced organic chemistry, March p 212Clayden 1st Edn p 1140 2nd Edn p 810Dr. F. Pradaux, Sheffield University
Baldwin’s rules for ring closure
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Nomenclature
3, 4,......7
Number Indicates the size of the ring being formed
1. Ring size
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The bond broken as the ring is formed is outside the new ring
X-
exo
XY Y-
X-Y X Y-
endo
2. Bond
The bond broken as the ring is formed is inside the ring
Nomenclature
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sp3 tetrahedral carbon tet
sp2 trigonal carbon trig
sp digonal carbon dig
3. Geometry
geometry of the carbon undergoing the ring closing can be describes as:
Nomenclature
Y
Y
Y
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For example.....
1
3 4
2
OH
OH
OH
5
5-exo-trig
2
3
1H2N
Br
3-exo-tet
O56
12
3
4
O
6-endo-dig
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Reactions can be favoured or disfavoured
•kinetic favourability of a reaction
• A disfavoured reaction does not mean that the reaction will not occur -just that it is more difficult
•Disfavoured cases require severe distortion of bond angles and distances
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Ideal bond angles
•Favoured cyclisations enable terminal atoms to achieve proper geometries
O
Nu-
= 109°
Nu
OH
Trigonal carbons(Bürgi-Dunitz)
YX-
X Y- = 180°
C C
X-
= 120°C C
Y
X
Y
Tetrahedral carbons(Walden inversion)
Digonal carbons
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Tetrahedral systems
-XY
X-
YX-
Y X- Y
X-
YX-
Y
X-
Y
5-exo-Tet3-exo-Tet 4-exo-Tet 6-exo-Tet
7-exo-Tet 5-endo-Tet 6-endo-Tet
12
351
23
5
6
7
1
2
3
1
2
3
1
2 3
4
4
4
5
6
4
1
2
3
45
6
1
2
3
4
all exo-tet cyclisations are favoured
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Trigonal systems
-XY
X-Y
X-
Y X- Y X-
Y
X-
Y
X-
Y
5-exo-Trig3-exo-Trig 4-exo-Trig 6-exo-Trig 7-exo-Trig
5-endo-Trig 6-endo-Trig
-XY
-X Y
X-
Y
3-endo-Trig 4-endo-Trig 7-endo-Trig
12
3
51
23
5
6
71
2
3
1
2
3
1
2 3
4
445
6
4
1
2
3
4
5
6
1
2
3
4
1
2
3
12
3
4
5
71
2
3
45
6
All exo-trig cyclisatons are favourable
5-endo trig are disfavoured!
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NH2
O
OEt 5-endo-trig
HN
OEt
O
NH2 OEtO
5-exo-trig
NH
O
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Exo-tet
X
Y
n
X lone pair C-Y * overlapattack at 180° angle possible
X n
Y
X lone pair C=Y *overlapattack at 109° angle possible
Exo-trig
Favoured exo-tet and exo-trig
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Disfavoured 5-Endo-trig
N
OOMeH
H
Bad alignment
N lone pair cannot reach * orbital Dünitz angle (109°) attack not possible
N
H H
O
OMe
Too far away
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Disfavoured 5-Endo-trig...iodocyclisation
•Iodocyclisation forms the disfavoured “anti-Baldwin” endo-trig product•WHY?1)Overwhelming attraction between nucleophile and electrophile2)No kinetically favoured alternative pathways- 4-exo-tet would be too strained
HO
O
I
3 eq I2, NaHCO3
MeCN
HO
I
Knight et.al. Tetrahedron Lett. 1998, 39, 8909
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however
TsHN OH
3 eq I2, K2CO3
MeCN
NTs
I
O
NHTs
I
5-endo-trig
5-exo-trig
OH
•5-exo-trig strongly favoured over the 5-endo-trig
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Digonal systems
-X -XY
X-
YX- X-
X-
Y
X-
Y
5-exo-Dig3-exo-Dig 4-exo-Dig 6-exo-Dig 7-exo-Dig
5-endo-Dig 6-endo-Dig
-XY -X Y
X-
Y
3-endo-Dig 4-endo-Dig 7-endo-Dig
YY
Y
12
35
6
7
1
23
4
5
6
71
2
3
1
2
3
1
2 3
4
44
5
6
5
1
2
3
4
5
1
2
3
4
5
12
34
1
1
1
1
63 3
22
4
All endo-dig are favoured
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Endo-dig rationale
O
O
Ar1
2
3
4 5
5-endo-Dig
O
O* inaccessible
Ovelap in the plane of the ring
Ar
•Alkyne has two π* orbitals-one in the plane of the ring
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-X -XY
3-exo-Dig 4-exo-Dig
Y
12
3 1
2 3
4
x x
Disfavoured 3- and 4-exo-dig
•Nucleophile cannot attack at the required 120° angle
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Exceptions to the Baldwin’s rules
•second row elements
Why?
•Long C-S bond•Sulfur has empty 3d orbitals
SH
OMe
Obase
S
OMe
O5-endo-trig
S
O
OMe
O
OH 5-endo-trig O O O OH
•cations
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Summary
Size Exo Endo
Tet Trig Dig Tet Trig Dig
3 X X
4 X X
5 X X
6 X
7
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Intramolecular endocyclic alkylation of ketone enolates
Baldwin, Kruse, JACS Chem Commun. 1977, 233
Nomenclature
enolexo or enolendo orientation of the enolate C-C bond
exo-tet or exo-trig with respect to the C-Y terminus
+ Y--O Y O
(Enolexo)-Exo-Tet
-O Y O
+ Y-(Enolendo)-Exo-Tet
6 to 7 Favoured3 to 5 Disfavoured
3 to 7 Favoured
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OBr
O O
5-enolendo
not observed
(Compare with disfavoured 5-endo trig)
Oxygen alkylation vs. Carbon alkylation
O Br O O
6-enolendonot observed
(Compare with favoured 6-endo-trig)
O
Y
C alkylations
180° attack
O alkylations
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OOO
MX X
M
•Oxygen alkylation -electrophile approaches in plane of the enolate
XOM
Carbon alkylation in 6-enolendo possible
•Perpendicular approach to the enolate
Oxygen alkylation vs. Carbon alkylation
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-O Y O
(Enolendo)-Exo-Trig
Y-
-O Y O
(Enolexo)-Exo-Trig
Y-
disfavoured 3 to 5 favoured 6 to 7
Favoured 3 to 7
Intramolecular aldol condensations
Baldwin, Tetrahedron, 1982, 38, 2939
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5-enolendo-exo-trig vs. 6-enolendo exo-trig
O
O
O O
O
O
O
O
O
+5-(Enolendo)-
exo-trig
6-(Enolendo)-
exo-trig
•6-enolendo-exo-trig exclusively formed.
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Summary
Exo-Tet Exo-Trig
Size enolendo enolexo enolendo enolexo
3 X X
4 X X
5 X X
6
7
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Just remember.....
1. Exo-tet and endo-trig favoured2. 5-endo trig disfavoured*
3. Endo-dig favoured
1. Enolexo endo-tet and trig are favoured
Endocyclic reactions
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N
O
Ph
Ph2
51
4
3
5-endo-trig*
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Other Than Nucleophilic Cases
• Radical Processes (homolitic):
• Cationic Processes:
3-exo-Trig
4-endo-Trig
6-endo-Trig
5-endo-Trig