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The Baldwin rules: revised and extended: Baldwin: Revised, Extended

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 Advanced Review

The Baldwin rules: revised

and extended
Kerry Gilmore,1 Rana K. Mohamed2 and Igor V. Alabugin2*

The Baldwin rules constitute one of the clearest examples of the success which
can be obtained through the application of stereoelectronic concepts to reaction
design. With thousands of examples, the predictive power of these rules is inar-
guable. However, time has revealed a number of exceptions and gray areas
within these rules, leading to extensions and revisions. In this review, we will
present an overview of how subsequent studies of ring closure have clashed with
several of Baldwin’s predictions, leading to the revision of some classes of ring
closure (alkyne cyclizations, electrophilic closures, etc.). We also discuss for
which the original rules were vague (epoxides) or absent (promoted cyclizations),
and the evidence revealed since Baldwin’s work that has allowed for a better
understanding of these ambiguities. With the concise summation of these
amendments, this review aims to present an overview of the understanding of
cyclization reactions to date. © 2016 John Wiley & Sons, Ltd
How to cite this article:
WIREs Comput Mol Sci 2016. doi: 10.1002/wcms.1261

INTRODUCTION understanding needed to achieve this goal was made

by Sir Jack Baldwin in 1976 with his seminal paper

T he diversity of chemical transformations can be

bewildering unless the key fundamental under-
pinnings responsible both for the dominant trends
and for the unexpected ‘exceptions’ are understood.
It is only through understanding can one gain control
over the inherent complexity of reaction design. Such
complexity comes to the fore in planning of cycliza-
tion reactions, the family of chemical processes where
the intrinsic preferences for chemical bond formation
are modified and attenuated by the geometric restric-
tions imposed by the cyclic nature of the bond form-
ing transition states.
With 90% of chemically individual molecules
discovered in nature containing a carbo- or heterocy-
clic subunit,1,2 the ability to control the outcome of a
cyclization reaction can be paramount to the success
of a synthesis. One of the key steps toward the
*Correspondence to: alabugin@chem.fsu.edu
1 predictions, have arisen. This overview summarizes
Department of Biomolecular Systems, Max Planck Institute of
Colloids and Interfaces, Potsdam, Germany
2
Department of Chemistry and Biochemistry, Florida State Univer-
sity, Tallahassee, FL, USA
Conflict of interest: The authors have declared no conflicts of inter-
est for this article.
entitled ‘Rules for Ring Closure.’3 This work provided
the terminology needed to discuss cyclization reac-
tions, combined experimental evidence and theory to
explain the currently observed selectivity trends, and
predicted the outcomes of modes of closure not yet
examined. Baldwin was able to do the latter because
he presented a reasonable hypothesis as to why a given
ring closures was favorable or not. The ‘why’ was
based on the proper alignment of molecular orbitals
and, as a result, the favorable trajectories for which a
nucleophile could attack a given functionality were
delineated. This work has inspired a wide range of
studies,4 experimental and theoretical, aimed at testing
and challenging these predictions. As a result, the
chemical community has gained a greater understand-
ing of an even broader set of cyclization reactions.
As can be expected with this greater under-
standing, a number of extensions and revisions to
Baldwin’s original rules, as well as the basis for his
these amendments, with the attempt to create a con-
cise summary of the understanding of cyclization
reactions to date. It is important to mention that clas-
sic cyclization reactions are not the only way to form
a cyclic structure (Figure 1). The other two cycle-

© 2016 John Wiley & Sons, Ltd

 Advanced Review
F I G U R E 1 | Comparison of the three classes of intramolecular
reactions utilized for cycle formation. Radical cyclizations were used as
an example: the scope of cyclizations is, of course, much broader,
including nucleophilic, electrophilic, and metal catalyzed processes.
forming types of reactions: pericyclic reactions5,6 and
cycloaromatizations,7,a have their own sets of rules
that will not be covered in this work.
BALDWIN RULES: TERMINOLOGY
AND CLASSIFICATION OF
CYCLIZATION MODES
In his seminal publication,3 Baldwin developed a uni-
fied classification of cyclization processes based on
three factors. As outlined in Figure 2, a cyclization is
characterized by three prefixes, the first of which pro-
vides the number of atoms in the forming ring and
can adopt any value ≥3. The second prefix, endo-
versus exo-, describes the position of the bond that
has to be broken in the cyclization, relative to the
forming ring (or the smallest of the rings when sev-
eral rings are formed simultaneously). Exo- indicates
that the breaking bond is outside of (exocyclic to) the
formed ring, while endo- indicates that the breaking
bond is inside of (endocyclic to) the new ring. The
last prefix, -tet, -trig, and -dig, refers to the hybridiza-
tion of the atom at the site of ring closure, -tet (tetra-
hedral) for sp3, -trig (trigonal) for sp2, and -dig
(diagonal) for an sp-hybridized atom.
BALDWIN RULES: PREDICTED
OUTCOMES
Figure 3 recreates the original depiction of the pat-
terns for the formation of three- to six-membred
cycles, the corresponding classification, and reaction
favorabilities. Overall, Baldwin’s predictions indi-
cated a preference for exo over endo modes for
© 2016 John Wiley & Sons, Ltd
wires.wiley.com/compmolsci
F I G U R E 2 | Baldwin’s unified classification of cyclization
processes based on three factors.
closures onto tetrahedral and trigonal targets. In con-
trast, digonal targets (alkynes) favored endo closures
with exo closure being likely for only larger cycles
(6 and 7).
Baldwin’s original treatment had solely dis-
cussed nucleophilic closures, but stated that the rules
applied to homolytic and cationic processes as well.
However, a well-known contemporary set of guide-
lines for radical reactions was developed by
Beckwith,8–10,b who combined steric and stereolec-
tronic factors to offer general predictions of favora-
ble cyclizations modes. A significant point of
divergence between the Baldwin and Beckwith rules
involves the cyclizations of alkynes. Endo-dig cycliza-
tions are favored by the Baldwin rules whereas the
Beckwith rules predict exo-dig cyclizations to be
preferred.
BALDWIN RULES: THE CENTRAL
HYPOTHESIS
The physical basis of the rules lie in the stereochemi-
cal requirements of the transition state for the vari-
ous ring closure processes. Favored reactions will be
those in which length and nature of linking chain
enables terminal atoms to achieve the required trajec-
tory to form the final bond of the ring. Disfavored
reactions would require severe bond angle and dis-
tance distortion, so the desired reaction coordinate
will be difficult (and, if available, alternative path-
ways will dominate).
Trajectories
One of the major defining factors in formulating the
cyclization rules is the identification of the ideal tra-
jectory for attacking the target functionality in the
ring closing step. Baldwin suggested three favorable
 WIREs Computational Molecular Science Baldwin: Revised, Extended

FI GU RE 3 | The original Baldwin rules: patterns of ring closure for three- to six-membered rings (endo-tet processes do not formally form
cyclic products but are included here because they should proceed through cyclic transition states as well). An updated and corrected version of
the rules will be given at the end of the present manuscript. (Reprinted with permission from Ref 3. Copyright 1976 Royal Society of Chemistry)

trajectories, one for each of the three common
hybridization states of the target, as shown in
Figure 4. For tet- and trig-cyclizations, the choices
were based on the backside attack preference of SN 2
reactions and on the just-published crystallographic
work of Bürgi and Dunitz, who identified the pre-
ferred angle of nucleophilic attack on a carbonyl.11
Of the two trajectories that would maintain the
subtended angle between the three interacting atoms
in digonal systems, Baldwin chose the one that corre-
sponds to an acute angle of attack β (60
, Figure 4
‘original’) rather than an obtuse angle (120
,
Figure 4 ‘refined’). This choice was based upon ‘the
X-ray work of Wegner12 and Baughman’13 as well as
a ‘general predominance for endo-ring closures in
digonal systems.’3
The latter statement was primarily derived from
the work of Kandil and Dessey,14,15 who compared
the reactivities of three carbanions generated in close
proximity to acetylenic groups at different geometri-
cal arrays—a divergent angle of 60
, parallel (angle
of 0
), and a convergent angle of 60
. No cyclic pro-
ducts were obtained when the angle was divergent
(1, Figure 5). For the parallel orbital arrangement
(2), however, the anionic species cyclized in a 5-
endo-dig fashion (5, Figure 5). Finally, when the
geometry of the two functional groups was fixed at a
convergent angle of 60
(3), the aryl anion cyclized
exclusively in a 5-exo-dig fashion (6, Figure 5).
At that time, the absence of the 4-exo product
in the ‘parallel arrangement’ case constituted the only
available experimental evidence which could be inter-
preted that an acute attack at the alkyne moiety was
favored. However, it is important to realize that this
example significantly distorts the intrinsic selectivity
due to the additional strain imposed by the polycyclic
core on the 4-exo product (one of the angles in the
four-membered ring would be constrained to 120
).
Furthermore, the observed lack of 6-endo cyclization
products in the less strained ‘convergent’ pattern is
inconsistent with the suggested preference for the
acute trajectory.

© 2016 John Wiley & Sons, Ltd

 Advanced Review
FI G URE 4 | The favored trajectories for cyclic closure in tetrahedral, trigonal, and digonal systems.
The proposed digonal trajectory also contra-
dicts the stereoelectronic requirements for nucleo-
philic attack at a π-bond. Basic MO considerations
suggest that a better trajectory for attack at the
alkyne π*-orbital is provided by the obtuse approach,
analogous to the Burgi-Dunitz trajectory for trig
cyclizations (Figure 4). Indeed, a substantial body of
experimental and computational evidence supports
this notion, indicating that the Baldwin rules for
alkynes needed to be redefined (vide infra).
REVISION 1: OBTUSE TRAJECTORY
FOR ALKYNES
In an early computational investigation of the acute
attack trajectory, Strozier, Carmella, and Houk cal-
culated transition states for a sterically unbiased
intermolecular case—attack of a hydride anion at
acetylene and ethylene.16,17,c Not only were the tran-
sition state energies found to be very similar for acet-
ylene and ethylene (16.7 and 16.6 kcal/mol) but the
angle of attack was also found to be quite similar for
the two substrates, with a CC-Nuc angle of 127
and
124
, respectively18—very different from the 60

acute attack suggested by Baldwin.3
Recent higher level calculations19–23 found the
same stereoelectronic preference, providing further sup-
port to the notion that the obtuse geometry provides
the best trajectory for nucleophilic attack at the triple
bond and that the transition state (TS) geometries for
nucleophilic addition to alkenes and alkynes are gener-
ally similar. The representative intermolecular attack
angles by three nucleophiles (CH3− , NH2− , and OH−)
on the triple bond of acetylene are shown in
Table 1.24 Although the angle changes from approxi-
mately 115
to 130
with the transition from an early
© 2016 John Wiley & Sons, Ltd
wires.wiley.com/compmolsci
F I G U R E 5 | Three examples used to define the original Baldwin
rules for alkynes. (a) With a ‘divergent angle’ of 60
, only the reduced
product is obtained. (b) A ‘neutral’ parallel geometry with the angle of
0
results in 5-endo-dig closure of the carbanion. (c) A ‘convergent’
geometry exclusively yields the 5-exo-dig product.
TS to a late TS, the data agree with the intrinsic
stereoelectronic preference for obtuse attack.
The basic stereoelectronic considerations that
support the obtuse nucleophilic attack trajectory can
be inferred from examining the nucleophilic trajec-
tory for intermolecular addition to alkynes (Table 1).
This approach avoids the interaction of incoming
nucleophiles with the nodal plane of the π*-orbital.
When this analysis is applied to the intramolecular
nucleophilic attack at the alkyne moiety (aka nucleo-
philic dig-cyclization), the obtuse trajectory translates
into stereoelectronic preference for the exo-attack, in
close analogy to that of trig-cyclizations.
It is also important to note that alkynes have
two orthogonal π-bonds, thus alleviating the need for
the nucleophile to deviate out of the plane in order to
reach the π*-orbital. Instead, the incoming reactive
 WIREs Computational Molecular Science Baldwin: Revised, Extended

TABLE 1 | Reaction Energies, Attack Angles, and LUMO Plots Visualizing the Arrangement of Alkyne π*-Orbital and Nucleophile Lone Pair for
the Parent Anionic Additions to Acetylene at the B3LYP/6-31+G(d,p) and M05-2X/6-31+G(d,p) Levels of Theory

Intermolecular Nucleophilic Addition to Acetylene

LUMO of TS
Nucleophile CH3− NH2− OH−
ΔEr (kcal/mol) −48.00 −34.57 −23.41
(−51.83) (−35.84) (−25.31)
Nu CC angle at TS and product TS: 120.5 (114.0) TS: 134.6 (122.5) TS: 132.3 (129.1)
P: 123.8 (123.4) P: 129.3 (128.7) P: 129.1 (121.7)
Nu C distance at TS (Å) 2.763 (2.606) 2.535 (2.435) 2.309 (2.206)
24
M05-2X data are given in parentheses.

center (radical, cation, anion, radical–cation, and

radical–anion) can attack the in-plane π-bond to
avoid the additional distortion penalty inherent to,
e.g., the 5-endo-trig process (Figure 6, top). How-
ever, even though this factor is likely to decrease the
overall distortion penalty for reaching an endo-dig
TS in comparison for the analogous penalty for an
endo-trig TS, the penalty does not disappear.
DFT analysis of nucleophilic closure24 revealed
that as the linker length increases, the obtuse angle of
the exo-attack decreases from 140
(3-exo) to 116

(5-exo) for carbanions, approaching the angle of
intermolecular attack (Table 1). For endo-closures
forming small cycles, the cyclic constraints impose an
acute angle for nucleophilic attack (76
for 4-endo F I G U R E 6 | Stereoelectronic differences between alkenes and
and 82
for 5-endo closures). Because of the increase alkynes arising from the presence of the in-plane π-system in alkynes.
in the formed cycle size, the angle of attack changes
to a more favorable obtuse trajectory in 6-endo-dig σ-aromaticity. Such cyclizations should be considered
closure (99
). As expected, 4-endo and 5-endo cycli- aborted pericyclic reactions (vide infra).25
zations have much earlier TSs than the less exother- In addition to computational data, emerging
mic competing 3-exo and 4-exo closures. experimental work started to provide evidence that
At the same time, the incipient C  C distance alkenes and alkynes are more similar than suggested
increases in the exo-series, indicating earlier TSs for by the Baldwin rules. We outline the key experimen-
the more exothermic cyclizations (3-exo < 4-exo < 5- tal results in the following sections.
exo). As will be discussed individually below, com-
parison of the intrinsic energies24,d shows that in
every case, independent of the nature of nucleophile EXPERIMENTAL EVIDENCE:
and alkyne substitution, exo cyclizations have lower EXO-DIGONAL CLOSURES OF
intrinsic barriers than their endo competitors. Inter- SMALL CYCLES
estingly, the intrinsic exo barriers change relatively
little (12–16 kcal/mol), indicating that such varia- 3-Exo
tions in the attack trajectory are well tolerated. It is In 2008, the 3-exo-dig version was discovered by John-
important to mention that anionic 5-endo cycliza- ston who coupled this cyclization with an exergonic
tions deviate from the general cyclization trends due fragmentation step that rendered the formation of a
to additional TS stabilization that originates from small strained cycle irreversible (Scheme 1).26 The

© 2016 John Wiley & Sons, Ltd

 Advanced Review wires.wiley.com/compmolsci

S C H E M E 1 | The 3-exo-dig cyclizations of enolates and propargylic alcohols.

necessity of the subsequent fragmentation exemplifies

the reason for the rarity of 3-exo-dig closures: the
kinetic and thermodynamic favorabilities do not align.
In other words, the stereoelectronics of ring closure are
appropriate, but the instability of the product makes
the reverse process (i.e., ring opening that proceeds
S C H E M E 2 | The 4-exo-dig cyclizations of the parent system are
through the same stereoelectronically favorable TS) very efficient for phenyl- and silyl-substituted alkynes.
faster.
rules and significantly less exothermic, is often faster
4-Exo than the alternative 5-endo-dig closure.35 Subsequent
experimental work confirmed these predictions; only
In the 1990s, the Bailey group reported regioselective
in the presence of an intramolecular interaction selec-
4-exo-27,28 and 5-exo-dig29,30 cyclizations of carba-
tively stabilizing the 5-endo TS could we obtain good
nions. Again, thermodynamic stabilization of the
yields of the 5-endo products (Scheme 3).36,37,f
product was important: alkynes without anion stabi-
Intrigued by the observation that the ‘favorable’
lizing substituents were unreactive (neither exo nor
reaction needed extra help to win over the ‘unfavora-
endo cyclization was observed) whereas Ph- and
ble’ 4-exo-dig closure, we took advantage of a timely
TMS-substituted substrates provided approximately
invitation to write a review on the Baldwin rules to
90% of, e.g., the 4-exo-dig product (Scheme 2).
undertake a systematic reevaluation of alkyne cycliza-
However, only in 2011 did a comprehensive
tions.38 Based on the revised stereoelectronic prefer-
study by Alabugin and Gilmore fully reexamine and
ences, we suggested a set of rules which reversed
redefine the rules for radical and anionic cyclizations
Baldwin’s predictions for alkyne cyclization (Table 2).
of alkynes.24 We turned to the Baldwin rules for guid-
Predictions for the radical processes are fully
ance when trying to understand the mechanism of
analogous with predictions provided by the Beckwith
reductive C1–C5 cyclizations of enediynes, used for the
rules.8 The new rules suggested that the exo-
design of efficient double-strand DNA photocleavers
cyclizations are generally preferred for both nucleo-
of hypoxic cancer tissues.31–33,e Among several possi-
philic and radical cyclizations.
ble mechanisms, our attention was drawn to radical
5-endo-dig closure, favorable according to the Bald-
win rules. To our surprise, however, there was only
one reported example of this reaction and it involved Nucleophilic Endo Closures
a Si-centered radical,34 not covered by the rules. Baldwin pointed out that the rules may not apply for
concerted electrocyclic processes.3 One unexpected
example where such limitations manifest themselves
Radical Endo Closures is the problem with 5-endo-dig and -trig closures.
Surprised by the scarcity of radical 5-endo-dig While these reactions are considered unfavorable due
cyclizations, we analyzed a variety of 4-exo-dig/5- to the difficulty in reaching the Burgi-Dunitz trajec-
endo-dig pairs computationally and found that the tories for the endo ring closures, a number of exam-
4-exo-dig cyclization, unfavorable according to the ples of nucleophilic closures, along with a few of

© 2016 John Wiley & Sons, Ltd

 WIREs Computational Molecular Science Baldwin: Revised, Extended

S C H E M E 3 | The first efficient 5-endo-dig radical closure of a carbon-centered radical.36,p

TABLE 2 | Revised Baldwin Rules for Digonal Cyclizations of barriers, facilitating these closures. The cyclic pro-
Anions and Radicals ducts of these reactions correspond to the cyclic TSs
of [2,3] sigmatropic shifts, e.g., the [2,3]-Wittig
Anionic 3 4 5 6
rearrangement,41 and such reactions can be classified
Dig endo- ✗ ✗ ✓ ✓ as ‘aborted pericyclic reactions’ rather than simple
exo- ✓ ✓ ✓✓ ✓✓ cyclizations. As Baldwin suggested, pericyclic reac-
tions should not be covered by the rules because the
Radical 3 4 5 6 aromatic nature of their TSs allows for closures
Dig endo- ✗ ✗ ✓ ✓✓ which are, geometrically speaking, unfavorable.
exo- ✓ ✓ ✓✓ ✓✓
✗: disfavoured; ✓: possible; ✓✓: favored modes of ring-closure. REVISION 2: ENDO-TET
radical cyclizations, of this type are known.35,39,40 A Atom Transfers
new explanation for the unusual features of anionic Although not classically defined as cyclizations and
5-endo cyclizations came from computational analy- not leading to the formation of a cyclic product,
sis of the parent anionic cyclizations.25 It was intramolecular reactions that involve endo-
revealed that the TSs for 5-endo-dig and 5-endo-trig substitution at a tetragonal center (i.e., n-endo-tet)
anionic ring closures are stabilized by the presence of also occur via cyclic TSs. Such reactions were also
a 5c,6e σ-aromatic orbital array involving the lone analyzed by Baldwin who predicted the original rules
pair at the nucleophilic center, the target alkyne to be unfavorable for n < 7 (Figure 8).
(or alkene) π bond, and a σCC bridge (Figure 7). This The validity of Baldwin’s models has been
stabilization lowers both the activation and intrinsic clearly shown for endo-tet cyclizations that involve

FI GU RE 7 | Left: 5-Endo cyclizations are aborted sigmatropic shifts. Additional stabilization to the cyclic structure analogous to the pericyclic
TS converts the latter into the global energy minimum. Right: (Top) Favorable symmetry for orbital interactions of the anionic lone pair, in-plane π
bond, and long C2-C3 σ-bond allows π* and nonbonding anionic orbital to couple via Through-Space (TS) and Through-Bond (TB) interactions
simultaneously. (Bottom) Cyclic delocalization and HOMO of the carbanionic 5-endo-dig TS.

© 2016 John Wiley & Sons, Ltd

 Advanced Review
F I G U R E 8 | Intramolecular substitutions in ‘tetrahedral systems’
are not classified as cyclizations but proceed via cyclic transition states
in which an atom/group is transferred. The original Baldwin rules
predict most endo-tet atom transfers as unfavorable.
small cycles. For example, anionic 1,2-shifts that
could formally proceed via a 3-endo-tet TS (Stevens42
and 1,2-Wittig, Meisenheimer rearrangements43) are
surprisingly complex. These processes are not con-
certed but rather involve homolytic bond cleavage
that leads to the formation of transient radical species
(Scheme 4). Furthermore, although they usually col-
lapse to the product quickly within a tight ion pair, a
small portion of such radicals can escape to give rise
to the typical radical products (i.e., dimerization).44
The complexities of these stepwise mechanisms
for endo-tet ‘cyclizations’ can be avoided through the
incorporation of nonfirst row atoms. The inclusion
of elements with larger atomic radii and bond dis-
tances can have a significant impact on the facility of
the reactive center to achieve the trajectory necessary
for substitution (α = 180
), which is why Baldwin
stated that the rules apply only to atoms in the first
S C H E M E 4 | Stepwise radical mechanisms have been invoked to explain formally 3-endo-tet processes.
© 2016 John Wiley & Sons, Ltd
wires.wiley.com/compmolsci
row of the periodic table.3 Indeed, exceptions due to
the presence of the heavier elements and longer
bonds in the cyclic TSs are well documented.
For example, the remarkable transformation of
an O- to C-carbanion (i.e., the upconversion of a
nucleophile), referred to as the 1,2-Brook
rearrangement,45,46 proceeds via a formal 3-endo-tet
step (Scheme 5). Not only are the C Si bonds longer
than bonds between the second row elements, but
the transient formation of hypervalent silicate inter-
mediates may provide another path for the apparent
violation of the 3-endo-tet and the reason for exclu-
sion of the heavier element.
As cyclic structures are not formed in endo-tet
processes, the same reaction products can be
obtained via an intermolecular route. In order to dif-
ferentiate between the intra- and intermolecular pos-
sibilities, the endocyclic restriction test (ERT) was
developed.47,48
In 1970, Eschenmoser47 explicitly used the
ERT to determine the mechanism of the base-
promoted methyl transfer shown in Scheme 6. Later,
King showed the transfer of the O-methyl group in
Scheme 7, if intramolecular, would proceed via an
eight-membered cyclic TS (i.e., 8-endo-tet). Although
slow for the top reaction, the endocyclic intramolecu-
lar transfer was found to be feasible in somewhat lar-
ger rings where the 9-endo-tet TS is unrestricted.
Interestingly, because of the much shorter dis-
tances in bonds to hydrogen, X H bonds for X =
carbon, nitrogen, and oxygen are not bound by the
restrictions set by Baldwin. The shorter X H bonds
allow for easier access to the 180
angle required for
nucleophilic/radical endo-tet cyclic TSs. Furthermore,
the nondirectional character of bonds to the
 WIREs Computational Molecular Science
S C H E M E 5 | The Brook rearrangement is a 1,2 shift driven by the
increased bond strength of the Si O bond (110 kcal/mol) compared
with the Si C bond (76 kcal/mol). Note that the possible involvement
of hypervalent silicate changes stereoelectronic requirement for the
ring formation.
S C H E M E 6 | Top: Since the 180
bond angle between the
nucleophile and leaving group cannot be achieved, the formation of
the product occurs via an intermolecular process. Bottom: In contrast,
exocyclic substitution is feasible intramolecularly.
hydrogen atom is easier to distort to a nonlinear
geometry. Houk has shown that such intramolecular
hydrogen atoms transfers (HAT) can even occur with
distinctly nonlinear geometries, usually 150–160
,
without a significant energetic penalty.49 These fac-
tors account for the ubiquity of radical 1,5-HAT50–52
making 6-endo-tet radical transfers of H-atoms actu-
ally quite favorable (Scheme 853).
Such selective transpositions of radical centers
has been used for the synthesis of complex molecules54
and for unlocking ‘carbene-like’ reactivity55 in cascade
alkyne transformations that correspond to the formal
insertion of an alkyne carbon into a C H bond. Mech-
anistically, the latter transformation (Schemes 8 and 9)
corresponds to a process where a selectively formed
vinyl radical abstracts hydrogen from the target C H
bond and the newly formed C-radical attacks the same
position at the vinyl moiety where the original radical
was generated (‘a boomerang process’).56
An early representative example by Curran51
illustrates that 1,5-HAT, after generation of a radical
at a remote site, can be used to produce C-centered
© 2016 John Wiley & Sons, Ltd
Baldwin: Revised, Extended
S C H E M E 7 | Favorable endo cyclization modes required transition
state ring sizes of at least nine atoms.
S C H E M E 8 | The formation of tetrahydrofurans via a sequence of
PhS˙ addition, 1,5-HAT, and 5-exo-trig cyclization.
radicals reliably from C H bonds—a structural unit
that is generally not suitable as a direct radical pre-
cursor and notoriously difficult to activate selectively
(Scheme 10).
Recently, Bertrand et al.57 presented a compre-
hensive ‘inventory’ of the less common 1,n-radical
translocations for n 6¼ 5 (i.e., 4, 6, 7). Typically, the
distance between the radical center and the hydrogen
atom to be abstracted should be ≤3 Å. The highly
distorted TSs for 1,2- and 1,3-HATs account for
their scarcity in literature. 1,4-HATs, although unu-
sual, have been reported and include an interesting
class of 1,4-HATs in diradicals characterized by a
‘self-terminating’ mechanism in which 1,4-HAT is
coupled with annihilation of all radical centers with-
out an external radical source or subsequent reaction
to form a ketene, a precursor to several synthetic tar-
gets (Scheme 11).58,59
EXTENSIONS TO THE RULES FOR
RING CLOSURE
While the original Baldwin rules primarily focused
on nucleophilic closures, there are several brief state-
ments in the work that allude to other types of
 Advanced Review wires.wiley.com/compmolsci

S C H E M E 9 | 1,5-HAT constitutes a crucial step in the radical cascade closure of ortho-alkynes.

closures, e.g., stating that the rules also apply to

homolytic and cationic processes and that the rules
for the opening of three-membered rings ‘seem to lie
between those for tetrahedral and trigonal systems.’
While these generalizations have been clarified in
subsequent years (vide infra), there are a variety of
cyclization classes where additional stereoelectronic
factors affect the reaction course. These cases have
resulted in several extensions to the original rules.

S C H E M E 1 0 | 1,5-HAT following initial generation of a vinyl

EXTENSION 1: TWO ORBITAL radical.
ARRAYS
Enolates
The first extension of the rules was performed by
none other than Baldwin himself when he expanded
this terminology to include those cases where two
orbital arrays need to be aligned in the cycle-closing
bond formation, such as the cyclizations of eno-
lates.60,61 If the enolate C C bond is exocyclic to the
ring being formed, the cyclization was referred to as
an ‘enolexo’ closure, while if the enolate is endocyclic
to the ring being formed, the process was designated
‘enolendo.’ It is important to note that enolate clo-
sure can occur at either the carbon or oxygen, and
the stereoelectronic requirements for each are differ-
ent due to the in-plane lone pair of the oxygen S C H E M E 1 1 | A Norrish 1 process is followed by self-terminating
(Figure 9). Baldwin’s rules for enolates were limited 1,4-HAT to form a closed shell intermediate in the synthesis of 1,22-
to exo-tet and exo-trig closures. 3- and 4-(enolendo)- dihydroxynitianes and fuscicoccane A-B ring systems.
closures (for both exo-tet and exo-trig modes) were
suggested to be unfavorable cyclization modes while electrophilic cyclizations where a cationic center is
5- and 6-(enolendo)- and 3- to 7-(enolexo)- were stabilized by the overlap with an adjacent lone pair,
deemed favorable. e.g., oxycarbenium and iminium ions [Y = O, N
(π-vinylexo) and (π-vinylendo), Figure 10].
Crich and Fortt have also distinguished
Other π-Systems between π-exo and π-endo closures in their discussion
The stereoelectronic considerations applied to eno- of five- and six-membered ring formation in the digo-
lates are also applicable to enamines and other allylic nal cyclizations of vinyl radicals.62 Note, however,
and heteroallylic systems. Both allylic and hetero- that here the π-system is not part of the reacting
allylic cyclizations can be included in an expanded orbital array but constrained perpendicularly to the
version of this classification (e.g., C/O/N-allyl, etc., attacking radical center. As such, we proposed to dif-
where the C, O, or N designates the nucleophilic ferentiate these two π-exo/endo systems by describing
site). One can also apply this classification to the orientation of the reactive center by adding new

© 2016 John Wiley & Sons, Ltd

 WIREs Computational Molecular Science
FI GU RE 9 | (Left) Distinction between C-enolexo and C-enolendo patterns for exo-tet cyclizations. (Right) Cyclizations of enolates can occur at
either the carbon or oxygen. The stereoelectronic restrictions are less stringent for oxygen.
prefixes, σ- and π- to the classification (Figure 10).38
For example, π-vinylexo/endo (D/E) refers to reactive
centers incorporated into the π-system (i.e., oxycarbe-
nium and iminium ions) and σ-vinylexo/endo (B/C)
refers to reactive centers perpendicular to the
π-system (i.e., vinyl anions/radicals). Aryl nucleo-
philes/radicals fall under the category of σ-vinylendo,
(C) closures and benzylic species fall under (π-viny-
lendo, H). The utility of motifs D and E is limited to
radical and electrophilic closures.
EXTENSION 2: THE GRAY AREA OF
EPOXIDES
Surprisingly, recognition of the special character of
new functional groups has not been expanded to
epoxides, another system with unique stereoelectro-
nic features. The stereoelectronic nature of epoxide
closures relative to cyclizations onto other π- or
σ-bonded systems can be understood by analyzing
the orbital symmetry of the epoxide LUMO (an ‘all
out-of-phase’ combination of the three in-plane
Walsh p-orbitals). Inspection of this orbital array
reveals the similarities between the breaking of an
epoxide’s banana bonds with the trajectories of exo-
tet closures and the crossing of nodal planes present
in endo-trig cyclizations (Figure 11). In addition, one
should keep in mind that TSs for strain-driven exo-
thermic reactions may be much earlier in epoxides in
comparison to tetragonal or trigonal systems.
© 2016 John Wiley & Sons, Ltd
Baldwin: Revised, Extended
In the original Baldwin paper, epoxides were
mentioned only briefly: ‘The rules for opening three-
membered rings to form cyclic structures seem to lie
between those for tetrahedral and trigonal systems,
generally preferring exomodes.’3 However, due to
their unique features, Baldwin’s original classification
is too ambiguous for cyclic closures onto epoxides,
reactions that are important for organic synthesis
and play a central role in the biosynthesis of ladder
polyether natural products.63,64 The generality of
Baldwin’s classification has led to much misunder-
standing and several reports of ‘anti-Baldwin’ reac-
tions, especially in field of enzyme reactions.65–67
Much of this misunderstanding has to do with the
improper classifications of cyclizations that lead to
fused products (Figure 12) as ‘endo-tet’ cyclizations.
Albeit a formally single bond is broken when a
cyclization is accomplished via attack at the epoxide
carbon with concomitant epoxide ring opening, it is
more appropriate to consider the whole epoxide moi-
ety as the functional group involved in this transfor-
mation (in the same way as two alkene carbons are
considered as one functionality). The stereoelectro-
nics of these processes are different from simple tet-
cyclizations.
This issue has been analyzed by Jamison and
coworkers who have pointed out that the use of
endo-tet and exo-tet for epoxide closures is a miscon-
ception as the breaking epoxide C O bond is located
outside the newly formed ring in both cases. Each
cyclization should be considered an exo-tet process.69
 Advanced Review wires.wiley.com/compmolsci

F I G U R E 10 | Extended classification of possible ring closure patterns separated into structural motifs. Top: isolated reactive center (‘X*’ can
either be a cation, anion, or radical). Center: the reactive center is orthogonal to the second π-system. Bottom: the reactive center is included in a
larger π-system which can be positioned either outside or inside the formed ring.

Only if both carbons of an epoxide are considered as
one functional group, similarly to an alkene, is the
endo/exo classification applicable, but then the classi-
fication should use the exo-trig and endo-trig (not
tet!) cyclizations as the reference point for the ‘spiro’
or ‘fused’ TSs, respectively (Figure 12). As ‘anti-Bald-
win’ enzymatic reactions of epoxides correspond
most closely to the 6-exo-tet/6-endo-trig cyclizations
(both of which are favorable), enzymes do obey the
stereoelectronic guidelines embodied by the extended
set of Baldwin rules!70
Although implicated in several biosynthetic
processes, ‘endo’-selective epoxide opening cycliza-
tions still present a significant challenge in reaction
design. The stepwise mechanism of the nucleophilic
endo-selective epoxide-opening cascade has been
shown to be promoted by water (Scheme 12).71
Furthermore, the rate and regioselectivity of the cycli-
zation improves as the cascade reaction proceeds, an
observation that was attributed to an enhanced
hydrogen bonding network with water with increas-
ing fused appendages.
The above stereoelectronic analysis can be
expanded to the formation of other small cycles. For
example, the synthesis of oxazetidine amino acids for
use in rapid amide ligations proceeds via a selective
4-exo-tet cyclization of a hydroxylamine-epoxide.72
The alternative mode of attack that would produce a
larger and less strained cycle is not observed. If one
considers the epoxide moiety as a trigonal system as
discussed above, the nonobserved pathway would
correspond to the unfavorable 5-endo-trig cyclization
that is slower than the ‘4-exo-trig’ alternative
(Scheme 13).

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 WIREs Computational Molecular Science
FI GU RE 11 | Comparison of exo-tet, endo-trig, and epoxide
cyclizations.
FI GU RE 12 | Nomenclature defining the two modes of
cyclizations onto epoxides. See Ref 68 for stereoelectronic analysis.
EXTENSION 3: ELECTROPHILIC
CLOSURES
As previously mentioned, in the original presentation
of the rules, Baldwin stated that the stereoelectronic
guidelines which rationalize nucleophilic ring clo-
sures ‘also applies to homolytic and cationic pro-
cesses.’3 However, the direct extension of the rules
for nucleophilic closure to the cyclizations of other
reactive intermediates without a reexamination of the
fundamental stereoelectronic factors would be a mis-
take. While it is certainly correct that reactive inter-
mediates other than nucleophiles have favorable
© 2016 John Wiley & Sons, Ltd
Baldwin: Revised, Extended
trajectories based on their stereoelectronics, the very
nature of the bond-forming interactions—which
define the favorable trajectories—is strongly depend-
ent on the reactive intermediate. As such, the guide-
lines cannot simply be ‘transferred’ from nucleophiles
to electrophiles. Separate guidelines had to be devel-
oped for attacking species of a different nature.
Why do the stereoelectronic requirements differ
for nucleophilic and electrophilic attacks? The most
important stabilizing two-electron interaction for a
nucleophilic attack is the interaction of nucleophile’s
HOMO with the substrate’s LUMO. Such interaction
is maximized by an obtuse angle of attack at a
π*-system (alkene or alkyne) or by a backside attack
at a σ* (C Y). Both of the above approaches also
minimize the destabilizing HOMO/HOMO interac-
tions (Figure 13). In contrast, attack of an electro-
phile at a π-bond (alkene or alkyne) is controlled by
a favorable 2e-interaction between the electrophile
LUMO and the π-bond HOMO. The latter interac-
tion favors an acute trajectory, which brings electro-
philes at the center of the π-bond on route to the
formation of a 3-center, 2-electron nonclassical cat-
ion (common species in carbocation chemistry). This
trajectory imposes no stereoelectronic restrictions
and should enable both endo and exo ring closures.
For example, the ubiquitous cationic 1,2-shifts
involved in the Wagner-Meerwein rearrangements
are topogically analogous to the unfavorable anionic
3-endo-tet process described above.73,74 The ubiquity
of cationic processes shows that front-side approach
is allowed for electrophilic attack at a σ-bond.
The analysis of the bond forming HOMO/
LUMO interactions suggests that cationic cycliza-
tions do not have stereoelectronic restrictions for
bond formation in the same way as their nucleophilic
counterparts. The cationic processes are generally
fast and controlled by the thermodynamic stability of
products, instead of the kinetics associated with
stereoelectronic stabilization or destabilization of TSs
embodied by the Baldwin rules.
In the case of a radical attack at a π-bond, a
nearly perpendicular trajectory is observed, as a com-
promise between the interactions of the SOMO with
both the π and π* alkene/alkyne orbitals.75 Note that
the intrinsic differences in the underlying stereoelec-
tronic stabilizations should make endo-cyclizations
more favorable for cationic species—and to some
extent electrophilic radicals—in comparison to simi-
lar anionic closures.
The following rules were suggested for digonal
closures on the basis of a still rather limited data set
(Table 3).38 As with the cyclizations of anionic/radi-
cal intermediates, 3-endo-dig closure is a disfavored
 Advanced Review wires.wiley.com/compmolsci

S C H E M E 1 2 | This selective epoxide-opening cascade is promoted by water in step-wise fashion in which the rate increases with each
consecutive closure.

S C H E M E 1 3 | Intramolecular 4-exo-tet/4-exo-trig epoxide

opening outcompetes the alternative 5-exo-tet/5-endo-trig cyclization
to form oxazetidine.

reaction, mostly for the thermodynamic reasons (high

strain in the product). For the same thermodynamic
reasons, 3-exo/4-endo cyclizations do not proceed to
completion but get frozen at the 3c,2e nonclassic cat-
ion stage. However, the cyclic products can be
formed efficiently under the right conditions upon
nucleophilic attack on the nonclassic species (NPEC
process, vide infra). The corresponding products can
even be obtained regioselectively, and these closures
are deemed ‘possible.’ While there are no examples
of electrophilic 4-exo- and 5-endo-dig closures in the
literature,75,g these cyclizations were predicted to be
difficult but potentially achievable under the right
combination of substituents and reaction conditions.
Finally, both 5-exo and 6-endo products are favora-
ble and can be obtained selectively, depending upon
substitution at the π-system and the nucleophile.
These rules should hold true for trigonal closures as
well. However, the respective tetragonal closures
have yet to be examined.
EXTENSION 4: PROMOTED
CYCLIZATIONS
There are two fundamentally distinct extensions that
exist for less reactive nucleophiles/electrophiles, called
Nucleophile-Promoted Electrophilic and Electrophile-
Promoted Nucleophilic closures (NPEC and EPNC,
respectively). NPECs, first introduced by Overman and
Sharp,76,77 occur in a formally electrophilic cyclization
when an acyclic cation/3c-2e complex is more stable
than either the exo- or endocyclic vinyl cation. Such
cyclizations are frozen ‘half-way’ and only occur when
F I G U R E 1 3 | Comparison of orbital interactions and the expected
regioselectivities for nucleophilic (left) and electrophilic (right)
cyclizations of alkynes. Dominant stabilizing interactions are shown
with straight arrows; secondary (stabilizing or destabilizing)
interactions are shown with dashed lines.
TABLE 3 | Revised Baldwin Rules for Electrophilic, NPE, and EPN
Digonal Cyclizations
3 4 5 6
Trig/Dig endo- ✗ ✓ ✓ ✓✓
exo- ✓ ✓ ✓ ✓✓
✗: disfavored; ✓: possible; ✓✓: favored modes of ring-closure.
EPNCs will be covered in the next section (‘Extension 4’).
a nucleophile attacks the opposite face of the π-system,
inducing bond formation between the π-system and the
cation. The umpolung of NPEC, where an external
electrophile coordinates to a π-system and the latter is
subsequently attacked by an internal nucleophile, has
been termed EPNC (Figure 14).38
Nucleophile-Promoted Electrophilic
Cyclizations
This mechanism provides the only thermodynamically
feasible path for endo-dig cationic cyclizations leading
to the formation of small cycles. While there exist a
number of examples for 3-exo/4-endo-dig closure onto

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 WIREs Computational Molecular Science
FI G UR E 1 4 | Stereoelectronics for NPE and EPN cyclizations.
carbocations, products are only observed in the pres-
ence of suitable nucleophiles.78–81 The bond-breaking
and bond-forming events were found to be
asynchronous,82 and the regioselectivity of these clo-
sures is determined by the substituents of the alkyne
(Figure 15).79,83
Larger cycles can also be formed using these
promoted cyclizations, taking the form of Prins-
type84,h or Richter85 cyclizations, among others. The
necessity of the nucleophile for cyclization was first
noted by Overman and Sharp, who found that the
6-(π-vinylendo)-endo-dig closure occurred only in the
presence of the iodide nucleophile.76 Similarly, alky-
nyl Richter cyclizations onto aryl diazonium salts are
assisted by external species.86–89 Interestingly, the
regioselectivity for these latter closures can be con-
trolled either with temperature90–92 or the nature of
the preexisting cyclic core (Scheme 14).86,93–97
S C H E M E 1 4 | External nucleophilies can also promote endo-digonal closures to form larger cycles.
© 2016 John Wiley & Sons, Ltd
Baldwin: Revised, Extended
Electrophile-Promoted Nucleophilic
Cyclizations—Effect of External
Electrophile on Trajectory
The umpolung of NPEC, where an external electro-
phile coordinates to a π-system—activating it for
intramolecular nucleophilic attack—has been
described as EPNC.38 Since a recent review by
Godoi, Schumacher, and Zeni provided comprehen-
sive coverage of EPN cyclizations,98 we only address
the common misconceptions and the unique features
of these reactions.
Although these relatively common cyclizations
are sometimes misleadingly referred to as ‘electro-
philic’ cyclizations, they are mechanistically different
from true electrophilic cyclizations. A true electro-
philic closure involves intramolecular bond forma-
tion between an electrophile (e.g., carbenium,
oxonium, and iminium ions) and a π-bond in cycle-
closing bond formation, generating an alkyl or vinyl
cation. In contract, EPNCs involve intramolecular
nucleophilic attack at the triple bond. The role of an
external electrophile (cationic metal, halogen, sele-
nium, etc.) is to coordinate to the π-bond that is sub-
sequently attacked intramolecularly by an internal
nucleophile (Figure 14). Because it is the nucleophilic
attack at a π-bond that closes the cycle, referring to
such closures as electrophilic is misleading, even
when these reactions do not proceed in the absence
of the electrophilic agent.
Another reason why EPN cyclizations are con-
sidered separately is that reactions which involve the
coordination of an external species do not fall under
the umbrella of the original Baldwin rules. Such coor-
dination modifies the nature of alkyne frontier
 Advanced Review
F I G U R E 15 | The competition between 3-exo-dig and 4-endo-dig
in NPE closures is controlled by substituents.
molecular orbitals (FMOs; Figure 13). For example,
even though in both nucleophilic and EPN closures
the nucleophilic attack on an alkyne follows a trajec-
tory which maximizes the overlap between the
LUMO of the acetylene and HOMO of the nucleo-
phile, the acetylene LUMO symmetry is very different
for the two cases.
This cyclization mode has been shown to be
effective in initiating an all endo-selective cascade,
which fuses a polycyclic aromatic backbone to the
electron-rich furan subunit,99 as shown in
Scheme 15.
Toste and coworkers100 described a Au(I)-cata-
lyzed isomerization/cyclization cascade with the cycli-
zation step electronically similar to the zwitterionic
S C H E M E 1 5 | The formal ‘all-endo’ metal-assisted EPNC cascade is initiated by EPN-5-endo-dig closure followed by multiple EPN-6-endo-dig
closures.
© 2016 John Wiley & Sons, Ltd
wires.wiley.com/compmolsci
Myers-Saito cyclization but proceeds by stepwise 6-
endo cyclization. The work was latter extended by
Liu and coworkers by trapping the intermediate oxo-
carbenium ion with an internal nucleophile (5-exo
fashion) as shown in Scheme 16.101
In 2013, Wang et al. reported that the Au(I)-
catalyzed C1–C5 cyclization of enediynes can also
be coupled with an internal nucleophilic attack
(Scheme 17). Interestingly, the authors proposed that
formation of the two new cycles proceeds in a con-
certed manner coupling 6-endo-dig with 5-exo-dig
cyclization.102
UNUSUAL SOURCES OF ENDO
SELECTIVITY
For ring closure of nucleophiles and radicals, exocyc-
lic closure is intrinsically favored. This holds true for
cyclization onto sp3-, sp2-, and sp-hybridized atoms.
As discussed above, there are several cases where this
exo-closure preference can be overridden: electro-
philic and promoted cyclizations. This is the result of
either different or manipulated molecular orbital
interactions as compared to the archetypal nucleo-
philic closure. There are, however, several cases
which lie outside of the exceptions listed above,
where unexpected stereoelectronic interactions can
circumvent intrinsic preferences or where the product
obtained does not necessarily result from the
obvious path.
 WIREs Computational Molecular Science Baldwin: Revised, Extended

S C H E M E 1 6 | Au(I)-catalyzed isomerization/cyclization cascade of skipped enediynes and extension via subsequent cyclization.

S C H E M E 1 7 | Intramolecular interception of cationic center in

Au-catalyzed C1-C5 cyclization of enediynes.

Case 1: 5-Endo-Trig Cyclizations

Geometric/stereoelectronic constraints may not be
solely decisive in the observed outcome of irreversible
ring closing reactions. An interesting approach to
highly substituted enantioenriched tri- or tetra-
substituted indanes was recently reported where an
enantioselective cation-directed cyclization reaction is
followed by a reaction with an electrophile.103 In this
system, the mode of cyclization is dictated by substi-
tution at the nucleophilic component of the reaction:
an ester led exclusively to 5-exo-trig cyclization onto
a carbonyl (Scheme 18, top) while a malonate exclu-
sively yielded the formally unfavorable 5-endo-trig
cyclization onto the C C π-bond (Scheme 18, cen-
ter). The kinetic favorability for the unusual 5-endo-
trig closure emerged in the more sterically biased sys-
tem that enforced a nonplanar enolate geometry.
Indeed, this is a nuanced system which provides an
interesting deviation from Baldwin’s original obser-
vations (Scheme 18, bottom).104
Case 2: Double Exo/Double
Fragmentation Cascades
A multitude of other cyclization reactions that are
reported as endo-selective processes may instead pro-
ceed via ring-expansion sequences. This pathway
takes advantage of the inherent exo-preference in
S C H E M E 1 8 | Top: A highly enantio- and diastereoselective
route to indanes via a 5-endo-trig cyclization catalyzed by a chiral
ammonium salt. Bottom: Baldwin’s original observation of only 5-exo-
trig cyclization product.
cyclizations via coupling of two exo-cyclizations with
a fragmentation. Several standard examples of cycli-
zation/fragmentation reactions that correspond to
this general scheme are summarized in Scheme 19.
Such rearrangements find useful applications
in synthesis.108–110,i,j For example, the switch from
5-exo- to 6-endo-trig selectivity in the radical cycli-
zation of aromatic enynes was recently probed via
the combination of experimental and computational
methods.111 In agreement with the predictions
above, 5-exo-trig closure was found to be the kineti-
cally preferred pathway. However, this cyclization
mode can be rerouted via homoallyl (3-exo-trig/frag-
mentation) ring expansion of the initially formed 5-

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 Advanced Review wires.wiley.com/compmolsci

S C H EM E 1 9 | Rearrangement routes subsequent to 3-exo-trig radical cyclization. The rate constants are from Ref 105–107.

exo product to afford the formal 6-endo-trig prod-
uct (Scheme 20).112
The above ring extension cascade does not
occur with alkynes. This limitation is unfortunate
because the 5-exo cyclization/homoallylic ring expan-
sion cascade of alkynes could potentially provide an
attractive direct synthetic alternative to the often
problematic 6-endo-dig ring closures that have to
compete with the stereoelectronically favorable 5-
exo-dig cyclizations. The effective implementation of
the radical version of this process is impossible in
alkynes where the products of 5-exo-cyclizations can-
not be ‘recycled’ into the 6-endo-products. The
impossibility of this pathway is a result of orbital
alignment; the vinyl radicals produced in exo-dig
cyclizations are constrained to orthogonality relative
to the target π-system. An efficient solution to the
design of formal endo-dig radical cyclizations of
alkynes involves a combination of endo-trig cycliza-
tions of alkenes (or its exo/exo analogue) with frag-
mentations (Scheme 21). Alkenes undergo
homoallylic expansion readily and, even though the
products of alkene cyclizations are not fully conju-
gated, a C C bond scission in the initial product can
lead to aromatization that provides the formal 6-
endo-dig product. This cascade illustrates how
alkenes can be used as stereoelectronically flexible
synthetic analogues of alkynes.111,112
Case 3: X-Centered Cyclizations
Addition of carbon centered radicals to unsaturated
C X bonds usually occurs at the carbon atom in the
favorable exo fashion. However, addition at the X
atom in several interesting examples has shown that
such processes are feasible and serve as an unusual
source of endo-selectivity. As shown in Scheme 22,
Menapace and Kuivila113 had reported the direct
reduction of alkyl halides by organotin hydrides, in
which γ-chlorobutyrophenone undergoes a selective
ring closure to generate 2-phenyltetrahydrofuran in
good yield. The 2-phenyltetrahydrofuryl radical

S C H E M E 2 0 | The observed 6-endo-trig selectivity in radical enyne cyclizations originates from 5-exo-trig cyclization followed by homoallylic
ring expansion.

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 WIREs Computational Molecular Science
S C H E M E 2 1 | Left: Stereoelectronic restriction on the 5-exo-
dig!6-endo-dig homoallylic ring expansion. Right: ‘Recycling’ of 5-
exo-trig products into 6-endo-trig products via homoallylic ring
expansion.
S C H E M E 2 2 | Direct 5-endo-trig onto the oxygen center of a
carbonyl group.
intermediate is stabilized by the benzene ring and
α-alkoxy group. Interesting features of such processes
have been recently reviewed.114
MANIPULATION OF SELECTIVITIES
The outcome of a cyclization reaction is not solely
influenced by the reactive species, ideal trajectory,
and/or the hybridization of the bond being broken.
The facility, or regioselectivity, of a ring closure is
often impacted by those groups adjacent to the inter-
acting atoms via modification of the ideal geometry
or by polarization. An additional factor often over-
looked is the exothermicity. While the Baldwin rules
are only valid for closures under kinetic control, to
discount thermodynamic factors in analyzing a given
cyclization is a mistake—it can influence the timeline
of the TS (early vs late) resulting in intrinsic prefer-
ences being ignored.
Case 1: Effect of Polarity
Orbital factors in the TS can also be modulated by
polarization of the π-bond by an appropriately posi-
tioned donor or acceptor substituent. For the
© 2016 John Wiley & Sons, Ltd
Baldwin: Revised, Extended
S C H E M E 2 3 | Effect of π*-orbital polarization on the magnitude
of stabilizing orbital interaction in a 5-exo-trig nucleophilic attack at
a π-bond.
substitution pattern illustrated in Scheme 23, the
exo-cyclization mode would be facilitated by a termi-
nal acceptor and disfavored by a terminal donor
group.
Through interesting SOMO–π* and HOMO–
LUMO interactions, nucleophilic radicals with low
lying LUMOs, such as acyl, oxyacyl, silyl, stannyl,
and germyl radical, are able to ‘masquerade’ as elec-
trophiles, allowing high levels of efficiency and regio-
control in the synthesis of heterocycles.115
Case 2: Distortions
Setting aside the more complex nonstatistical
dynamics analysis of reaction trajectories of
Carpenter,116,117,k additional factors have to be con-
sidered in analyzing the overall energy landscape on
the way from an acyclic reactant to a cyclic product.
In addition to the stabilizing two-electron bond-
forming interactions, one should also consider the
destabilizing effects associated with the deformation
of acyclic reagents from their ideal geometries needed
in order to reach the TS.118 The energy cost for
deviations from a reactive center’s ideal geometry,
pyramidalization of alkenes119 and bending in
alkynes, as well as strain in the bridge should be
taken into account.
Distortion at the Reactive Intermediate
Center (Anion vs Radical vs Cation;
Carbon vs Heteroatom)
Although the original Baldwin rules concentrated on
the orientation and nature of the breaking bond
(both exo/endo and tet/trig/dig notations refer to this
bond), the requirement of orbital alignment applies
to both partners. In particular, the stereoelectronic
properties of the attacking orbital and its orientation
in space can impose a significant effect on the effi-
ciency and regioselectivity of cyclizations. Baldwin’s
first extension of the rules into enolexo and enolendo
cyclizations illustrates this point very well.
 Advanced Review
The effect of the nature of the attacking atoms
on the preferred attack trajectories is not well under-
stood but deserves a more careful study in the future.
The flexibility of carbon-centered reactive intermedi-
ates has been examined by Jemmis et al., who sug-
gested that carbanions are the most flexible reactive
intermediate, whereas pyramidalization of cations
leads to a significant energy penalty.120 Comparing
heteroatoms, one would expect that the presence of
the two lone pairs at a neutral oxygen atom may
increase the stereoelectronic flexibility relative to an
analogous nitrogen nucleophile with a single lone
pair, where stereoelectronic adjustments are mostly
limited to rehybridization.121,122
Along these lines, it is interesting to note that
after suggesting the initial preferred angle of attack
of 105  5
at a carbonyl moiety by nitrogen nucleo-
philes, Bürgi et al. performed the same analysis for
an oxygen nucleophile attacking a carbonyl
(O  C O) and found that the approach angle varied
in the broad region of 90
–130
with the strongest
interactions occurring at an approach of about
110
.123
The significance of the reactive center is clearly
reflected in the 5-exo-trig closures of N, C, and O-
centered radicals whose rate constants span at least
5 orders of magnitude. Interestingly, the reactivity
does not follow the order expected from position in
the Periodic Table and electronegativity
(N < C < O, Figure 16).124 According to Walton
and coworkers, these data illustrate the predomi-
nance of C-radical chemistry in the cyclization
design. Addition of N-radicals to alkenes is just too
slow. However, the rates for O-radicals are suitably
high but suffer from the competition with β-scission
forming either CO2 or a carbonyl compound.
The computational investigation of these trends
suggested that increased rigidity of reacting nitrogen
species can be the reason for this counterintuitive
order.125 Interestingly, the computational data sug-
gest that carbon centered radicals engage in the bond
forming interactions with the target π-bond at the
larger distances than their nitrogen and oxygen ana-
logues. The electronic reasons for this difference
between the C-centered and heteroatomic radicals
are intriguing. The apparent impediment for the for-
mation of C X bonds (X = O, N) that does not exist
for X = C may originate from several sources. For
example, formation of C N and C O bonds
requires rehybridization at O and N atoms that have
to redirect some of their s-character from their lone
pairs to the new C X bonds. It is not clear at the
moment how large such rehybridization penalty may
be but it is clearly unfavorable as a consequence of
© 2016 John Wiley & Sons, Ltd
wires.wiley.com/compmolsci
F I G U R E 1 6 | Experimental Arrhenius activation energies, E‡
(kcal/mol) for 5-exo-trig cyclizations of selected O, C, N radicals.
Bent’s rule.121 Alternatively, the transformation of an
X-centered radical to a C-centered radical during the
cyclization leads to the loss of favorable geminal
delocalization between radical center and the lone
pair(s) of X. The latter occurs only when X is a heter-
oatom with a lone pair (N, O). These two factors
may provide alternative explanations to why carbon
radicals display higher reactivity than their heteroa-
tomic analogues.
Distortion of the Target π-System
The distortion of a π-system has a strong influence
on ring closures. Specifically, it has been shown
experimentally126 and computationally for both
alkenes127–129 and alkynes130–134,l,m that the LUMO
is disproportionately lowered with respect to the
increase in the energy of the HOMO. A significant
difference between alkynes and alkenes is that upon
trans-bending, the LUMO of acetylene drops in
energy two to three times faster than that of ethylene.
While the LUMO drops in a bent TS, there is an
increase in the charge-transfer and electrostatic inter-
actions, which is the cause of the increased reactivity
of acetylenes over ethylenes toward nucleophilic
attack. As there is very little effect on HOMO ener-
gies, no ‘driving force’ for bending is present upon
interactions with electrophiles.130 Thus, the distor-
tion of a π-system selectively facilitates cyclizations
involving nucleophiles or nucleophilic radicals.
In a detailed computational analysis of ‘strain-
promoted’ click reactions with phenyl azide, Houk
et al.132 have shown that the distortion of the alkyne
moiety in cyclooctyne can provide up to 60% of the
barrier decrease (4.6 of 8 kcal/mol).135–140 Alabugin
and Manoharan estimated the energy cost for alkyne
bending along the Bergman cyclization pathway,
comparing hex-3-ene-1,5-diyne with cyclic enediynes.
While a significant reactant destabilization (~13 kcal/
mol) is observed upon constricting the parent ene-
diyne with the nine-membered cycle, the acetylene
 WIREs Computational Molecular Science
S C H E M E 2 4 | The unusual 5-endo-trig cyclization is
photochemically facilitated via access of an excited twisted alkene.
bond breaking was found to be of only minor impor-
tance.141,142,n
Photoexcitation of the same aromatic enynes to
a triplet state creates a unique stereoelectronic situa-
tion, in which the alkene π-bond electrons are
uncoupled as an orthogonal diradical species. This
change removes the stereoelectronic restrictions on
the usually unfavorable 5-endo-trig cyclization and
merges it with 5-exo-dig closure. The 1,4-diradical
product of the C1−C5 cyclization undergoes internal
H-atom transfer that is coupled with the fragmenta-
tion of an exocyclic C C bond. This sequence pro-
vides efficient access to benzofulvenes from enynes,
in turn, uncovering the last missing example of the
four archetypical cycloaromatizations of enediynes
and enynes (Scheme 24).143
The above example shows that unique elec-
tronic and structural properties of excited states, in
combination with their high energy, may offer new
ways to control selectivity of the ring-forming
processes.
Deviation from Ideal Trajectories
The favorability of a cyclization mode depends
strongly on how far reactions can deviate from the
previously discussed trajectories without an insur-
mountable increase in activation energy, which
brings to question whether one should consider an
ensemble of trajectories instead of a single preferred
path.144 Historically, there were conflicting views on
this problem. For example, the ‘orbital steering’ the-
ory, related to enzymatic reactions, proposed that a
10
misalignment of reactant groups relative to an
© 2016 John Wiley & Sons, Ltd
Baldwin: Revised, Extended
F I G U R E 17 | Aromatic stabilization of the 6-endo-product masks
the stereoelectronic preference for the 5-exo-dig radical closure.
ideal orientation would result in a large decrease in
rate,145–147 something that has been disputed in sub-
sequent literature.148,149
Probing such effects in model systems, Menger
and coworkers investigated lactonization reactions in
a rigid norbornyl system. By exchanging positions of
the hydroxyl and carboxylic acid moieties, the trajec-
tory angles were changed by 10
, yet nearly identical
rates of lactonization were obtained, demonstrating
that angular displacement of a few degrees is not
kinetically significant.100 Lipscomb et al. also found
that potential energy surfaces for carbonyl additions
‘point strongly to a highly deformable TS.’ For exam-
ple, the addition of methanol to formic acid occurs
via a reaction ‘funnel’ that occupies approximately
18% of the hemispherical surface centered at the car-
bonyl carbon.150 Our calculations also found little
change (12.4–16.2 kcal/mol) in the intrinsic barriers
of carbon radical 3-exo, 4-exo, and 5-exo-dig closure
onto methyl substituted alkynes, even though the
angle of attack in the TS ranges from 140
(3-exo) to
116
(5-exo),24 further suggesting that deviation
from the ideal intermolecular trajectory is tolerated.
Effect of Thermodynamic Factors
The kinetic preferences described by the Baldwin
rules are not applicable to transformations that pro-
ceed under thermodynamic control. However, even
under kinetic control, thermodynamic factors can
modify reactivity in two ways. First, exothermic reac-
tions have early, reactant-like TSs and consequently
require less distortion from the reactant geometry to
reach the optimal bond-forming trajectories. Second,
thermodynamic contributions directly lower activa-
tion barriers of exothermic cyclizations.151 Consider
the 5-exo/6-endo competition shown in Figure 17.
The two reactions have almost identical activation
 Advanced Review wires.wiley.com/compmolsci

F I G U R E 18 | Baldwin’s nomenclature for cyclization reactions and the refined list of favorable and unfavorable modes of nucleophilic and
radical cyclization (Rules for Ring Closure). Favorable reactions are boxed with solid lines, the borderline reactions which require additional
assistance are boxed with dashed lines. The original Baldwin rules for alkyne cyclizations are changed as suggested by Alabugin and Gilmore.24

barriers (difference of 0.2 kcal/mol). However, the
aromatic stabilization gained in the product is suffi-
ciently effective in masking the intrinsic trends arising
from orbital alignment requirements. Marcus dis-
section can be used to estimate barriers for the situa-
tion where 5-exo and 6-endo-dig cyclizations would
have identical exothermicities, revealing that without
thermodynamic bias, the 6-endo cyclizations barrier
would be much higher (~15 kcal/mol) than that for
the 5-exo closure (~5 kcal/mol).152,o
CONCLUSION
The long evolution of the cyclization rules has led to
the set of guidelines shown above (Figure 18). These
rules are applicable for nucleophilic and radical cycli-
zations. A more detailed version of rules for alkynes
is available in the literature.38 General rules for
cations are not useful because cationic cyclizations
have no stereoelectronic restrictions and are, to a
large extent, controlled by thermodynamic factors.
Rules for EPNC are not shown for similar reasons
(no stereoelectronic penalty for endo-cyclizations)
and are limited to molecules containing π-systems
capable of coordination with external electrophiles.
This includes reactions catalyzed by transition
metals, as multiple new reaction modes are opened
by the unique electronic features of metal centers.
Baldwin’s rules have been of paramount signifi-
cance for the discussion and understanding of cycli-
zation reactions. Such predictions have guided a
large body of experimental research and catalyzed
the development of more accurate theoretical models.
In turn, this has led to a better understanding of the
underlying stereoelectronic principles for the forma-
tion and cleavage of chemical bonds in cyclizations,
undoubtedly one of the important class of chemical
transformations. Since 1976, the continuous effort of
several generations of organic chemists has led to the
extension and revision of Baldwin’s original rules.
While recent reexamination has allowed for the recti-
fication of our understanding of cyclization reactions
as well as reconciliation with experimental evidence,
gray areas still remain and present a challenge wor-
thy of future examinations.
NOTES
a
For a recent review on cycloaromatization reactions, see
Ref 7.
b
For an earlier work, see: Ref 9.
c
See also: Ref 17.

© 2016 John Wiley & Sons, Ltd

 WIREs Computational Molecular Science
d k
The intrinsic barriers were estimated via removal of ther-
monamic contribution to the activation barrier using Mar-
cus theory (vide infra).
e l
Applications: Ref 31.
f
Favorable of 4-exo-dig radical cyclizations: Ref 37.
g
Electrophilic cyclizations should not be confused with
electrophile-assisted cyclizations where electrophile coordi-
nates to a π-bond and ring closure originates from a nucle-
ophilic attack at the other face of the π-bond. See the
following section for a more detailed discussion.
h o
For a recent review, see: Ref 84.
i p
For conversion of phenols to derivatives of benzoic acids
via 3-exo-tet mediated O–C transposition, see: Ref 108.
j
See also: Ref 110.
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