Baldwin’s Rules
Nadia Fleary-Roberts02/05/12
•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
Nomenclature
3, 4,......7
Number Indicates the size of the ring being formed
1. Ring size
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
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
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
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
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
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
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!
NH2
O
OEt 5-endo-trig
HN
OEt
O
NH2 OEtO
5-exo-trig
NH
O
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
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
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
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
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
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
-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
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
Summary
Size Exo Endo
Tet Trig Dig Tet Trig Dig
3 X X
4 X X
5 X X
6 X
7
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
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
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
-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
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.
Summary
Exo-Tet Exo-Trig
Size enolendo enolexo enolendo enolexo
3 X X
4 X X
5 X X
6
7
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
N
O
Ph
Ph2
51
4
3
5-endo-trig*
Other Than Nucleophilic Cases
• Radical Processes (homolitic):
• Cationic Processes:
3-exo-Trig
4-endo-Trig
6-endo-Trig
5-endo-Trig
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