Stereoretentive chlorination of cyclic alcohols catalyzed by titanium(IV) tetrachloride: Evidence for a front side attack mechanism

Article abstract of DOI:10.1021/jo3023439

A mild chlorination reaction of alcohols was developed using the classical thionyl chloride reagent but with added catalytic titanium(IV) chloride. These reactions proceeded rapidly to afford chlorination products in excellent yields and with preference for retention of configuration. Stereoselectivities were high for a variety of chiral cyclic secondary substrates including sterically hindered systems. Chlorosulfites were first generated in situ and converted to alkyl chlorides by the action of titanium tetrachloride which is thought to chelate the chlorosulfite leaving group and deliver the halogen nucleophile from the front face. To better understand this novel reaction pathway, an ab initio study was undertaken at the DFT level of theory using two different computational approaches. This computational evidence suggests that while the reaction proceeds through a carbocation intermediate, this charged species likely retains pyramidal geometry existing as a conformational isomer stabilized through hyperconjugation (hyperconjomers). These carbocations are then essentially "frozen" in their original configurations at the time of nucleophilic capture.

Full text of DOI:10.1021/jo3023439

Article
pubs.acs.org/joc
Stereoretentive Chlorination of Cyclic Alcohols Catalyzed by
Titanium(IV) Tetrachloride: Evidence for a Front Side Attack
Mechanism
Deboprosad Mondal,† Song Ye Li,† Luca Bellucci,*,‡ Teodoro Laino,§ Andrea Tafi,∥ Salvatore Guccione,⊥
and Salvatore D. Lepore*,†
†Department of Chemistry, Florida Atlantic University, Boca Raton, Florida 33431, United States
‡Center S3, CNR Institute of Nanoscience, Via Campi 213/A, I-41125 Modena, Italy
§IBM Zurich Research Laboratory, CH-8803 Rueschlikon, Switzerland
̈
∥Dipartimento Farmaco Chimico Tecnologico, Universita
̀
degli Studi di Siena, I-53100 Siena, Italy
⊥Dipartimento di Scienze del Farmaco, Universita
̀
degli Studi di Catania, I-95125 Catania, Italy
S
* Supporting Information
ABSTRACT: A mild chlorination reaction of alcohols was developed using the classical
thionyl chloride reagent but with added catalytic titanium(IV) chloride. These reactions
proceeded rapidly to afford chlorination products in excellent yields and with preference
for retention of configuration. Stereoselectivities were high for a variety of chiral cyclic
secondary substrates including sterically hindered systems. Chlorosulfites were first
generated in situ and converted to alkyl chlorides by the action of titanium tetrachloride
which is thought to chelate the chlorosulfite leaving group and deliver the halogen nucleophile from the front face. To better
understand this novel reaction pathway, an ab initio study was undertaken at the DFT level of theory using two different
computational approaches. This computational evidence suggests that while the reaction proceeds through a carbocation
intermediate, this charged species likely retains pyramidal geometry existing as a conformational isomer stabilized through
hyperconjugation (hyperconjomers). These carbocations are then essentially “frozen” in their original configurations at the time
of nucleophilic capture.
nistically through a double inversion in the presence of
nucleophilic solvents. For secondary chiral alcohols, whether
this reaction proceeds via an internal nucleophilic substitution
(SNi) with stereoretention through ionic or concerted
mechanism is still under debate.6
INTRODUCTION
■
Though often a final product in itself, alcohols are among the
most common and important synthesis intermediates in
organic and medicinal chemistry lending importance to the
search for mild and high-yielding functional group intercon-
versions for this compound class.1 In this regard, the chloro-
dehydroxylation of aliphatic alcohols has long been recognized
as a valuable transformation prompting the development of a
plethora of techniques2 including the classical thionyl chloride
reaction.3 The challenging aspect in the development of these
reactions with chiral alcohols often centers on issues of
stereospecificity attracting the attention of numerous research-
ers in the past decade.4
Thionyl chloride is widely used in organic synthesis
especially for the conversion of alcohols to their corresponding
chlorides often under reflux conditions. This reagent is often
preferable to other reagents due to its gaseous byproduct (SO2)
for simplified purification. Excess thionyl chloride also can be
readily removed by distillation or evaporation. However, this
reaction often requires less than mild conditions, thus limiting
its application in the synthesis of delicate molecules. Traditional
alcohol chlorination reactions with thionyl chloride are thought
to involve either inversion or retention of configuration
depending on the involvement of the reaction solvent.5 In
these systems, retention of configuration is achieved mecha-
For several years, we have been interested in the develop-
ment of highly efficient leaving groups containing chelating
units capable of attracting incoming nucleophiles. In our
previous study, we demonstrated that the halogenations of
cyclic secondary alcohols containing nucleophile assisting
leaving groups (NALGs) react at greatly accelerated rates
with predominant retention of configuration.7 Following a
similar line of thinking, we have recently developed a new one-
pot mild amidation method using an in situ formed
chlorosulfite, derived from thionyl chloride.8 As part of that
amidation work we observed a tendency of titanium(IV)
species to catalyze the conversion of chlorosulfites to chlorides
at low temperatures. Herein we describe these findings and
further explore the preference in this chlorination reaction for
retention of configuration with cyclic alcohols.8 To shed light
on the reaction mechanism, we also include our computational
Special Issue: Howard Zimmerman Memorial Issue
Received: November 1, 2012
Published: January 8, 2013
© 2013 American Chemical Society
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investigation aimed at weighing the most probable paths of the
reaction through the characterization of their transition states
(TS) using density functional theory (DFT).
Table 1. Generality Study of One-Pot Chlorination of
Various Alcohols: All Chiral Alcohols Lead to Chlorination
Products with Exclusive Retention of Configuration
RESULTS AND DISCUSSION
■
Chlorination Studies. Owing to its propensity to form
hydride shift and elimination products, we began our
chlorination studies with l-menthol. This alcohol was first
treated with thionyl chloride at 0 °C to form the chlorosulfite,
which remained stable at this temperature as well as at room
temperature even after 24 h. The subsequent addition of
catalytic amounts of TiCl4 led to the chlorinated product with
retention of configuration with no tertiary chloride product
observed (Scheme 1). In general, these reactions gave product
Scheme 1. Chlorination of l-Menthol with SOCl2 and
Catalytic TiCl4
in high yields within 15 min at 0 °C with as little as 10 mol % of
TiCl4. When the reaction was cooled to −78 °C, after
chlorosulfite formation, the chlorination reaction time increased
to over 2 h even with 200 mol % of the titanium reagent.
Preliminary data also reveal that the present titanium(IV)
methodology can be extended to bromination. For example, the
bromide of l-menthol was obtained in 81% yield with complete
retention of configuration using SOBr2 and TiBr4 (10%) at 0
°C in dichloromethane.9
The use of catalytic TiCl4 with chlorosulfites was then
explored for a variety of cyclic secondary alcohols. Yields and
stereoselectivities were high in all cases, including traditionally
problematic sterically hindered systems (Table 1). As with
menthol, nearly complete retention of configuration was also
observed for many chiral cyclic alcohols (entries 6−10).10
Under these catalytic conditions, the chlorosulfites of tertiary
alcohols led to mixtures of elimination and chlorination
products with the exception of 1-admantanol, which afforded
only chloride product in 88% yield (entry 5). It should be
noted that 2-methylcyclohexanol (as well as l-menthol) gave no
tertiary chloride product, which would have been expected if a
classical carbocation mechanism were operative (entry 6).11
We initially found cis-3,3,5-trimethylcyclohexanol and β-
cholestanol to give some inversion product using our catalytic
conditions. Under these conditions (10% TiCl4), the
trimethylcyclohexanol and cholestanol derivatives gave 12%
and 29% inversion products, respectively. However, when the
reaction concentration was diluted (from 1.0 to 0.1 M) and
excess equivalents of TiCl4 were employed, the chlorination
reaction gave only products with retention of configuration
(Table 2).
a
b
c
Isolated yields. Yield based on NMR. For exclusive stereoretention,
d
2.0 equiv of TiCl4 was required. For exclusive stereoretention, 5.0
equiv of TiCl4 was required.
Table 2. Chlorination of cis-3,3,5-Trimethylcyclohexanol (7)
and β-Cholestanol (9)
b
conc
(M)
temp
time
(h)
TiCl4
yield
(%)
a
entry ROH
(°C)
(equiv)
ret/inv
7.1:1.0
1
2
3
4
5
6
7
8
9
7
7
7
7
9
9
9
9
9
1.0
1.0
0.1
0.1
1.0
0.1
0.1
0.1
0.1
0
0
5.0
1.0
0.10
2.0
75
80
80
75
88
90
92
80
72
ret only
ret only
ret only
2.5:1.0
0
3.0
2.0
−78
0
15
2.0
0.25
0.25
10
0.10
0.10
2.0
0
2.5:1.0
−78
0
2.5:1.0
0.25
0.25
5.0
ret only
ret only
Our chlorination studies of the cis/trans isomers of 3-
methylcyclohexanol and 4-methylcyclohexanol (Tables 3 and
4) led to mixtures of products. Specifically, we observed a small
amount of inversion products along with varying amounts of
hydride shift products. As with other substrates, an excess of
TiCl4 (2 equiv) seemed critical for optimal results. Additional
studies revealed that improved yields of stereoretentive
products can be achieved at colder temperatures (−78 °C)
0
10
a
b
Retention/inversion ratios determined by NMR. Isolated yields.
and a reaction concentration of the alcohol substrates
maintained at 0.1 M. For example, cis-3-methyl cyclohexanol
(12) led to a 7:1 ratio (retention: inversion) of chlorination
products with catalytic TiCl4 (10%) at 0 °C (Table 3).
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Article
here, one would expect that both trans- and cis-alcohols would
lead to the same product distribution which is not the case
here.13
Table 3. Chlorination Results with trans-3-
Methylcyclohexanol (11) and cis-3-Methylcyclohexanol (12)
Our study of 4-methylcyclohexanols led to similar outcomes
as the 3-methyl isomer system (Table 4). Trans-isomer 17 in
this case was transformed in reasonable selectivity to trans-
chlorinated product 16. In an attempt to achieve exclusive
retention of configuration, we performed extensive optimiza-
tion resulting in a 7.5:1 product ratio in favor of stereo-
retention. Under similar conditions, cis-isomer 18 gave cis-
product 15 exclusively along with a nearly equal amount of
hydride-shift isomer 13. While our computational studies in the
present work will only include a detailed analysis of the trans-4-
methylcyclohexyl system, we note that the energy of the
transition state involving cis-substrate 12 was the most stable
(by 1.35 kcal/mol) of all the modeled transition states for 3-
and 4-methylcyclohexyl isomers. This energetic preference may
explain why only cis-3-methyl isomer 12 led to complete
retention of configuration (Table 3).14
b
conc temp
time
(h)
TiCl4
yield
(%)
a
entry ROH (M) (°C)
(equiv) 13:14:15:16
1
2
3
4
5
6
12
12
12
12
11
11
1.0
1.0
0.1
0.1
0.1
0.1
0
−78
0
0.50
8.0
0.10
2.0
2.0
2.0
2.0
2.0
5.0:36:1.0:0
1.1:11:1.0:0
4.4:52:1.0:0
ret only
75
73
78
70
62
65
0.50
12
−78
0
0.50
4.7:1.1:4.8:1.0
1.1:1:1.0:0
−78
12
b
a
Ratios determined by NMR. Isolated yields. Relatively low yields
likely due to product volatility since NMR analysis of crude indicates
near-quantitative conversion to the corresponding chloride.
In our previous studies involving stereoretentive Ritter
amidation reactions, we only observed stereoretentive results
with cyclic secondary alcohols. As will be discussed below, we
believe the current method is also mechanistically limited to
cyclic secondary alcohol systems. Nevertheless, a limited study
was performed on a nonracemic acyclic alcohol (Table 5).
Starting with (S)-2-octanol (19), three chlorination products
were observed resulting from direct substitution (20) as well as
a hydride shift pathway (21 and 22). The hydride shift product
could not be separated from the direct substitution product,
and thus, its configuration could not be determined. However,
our studies in a related system involving acyclic substrates
suggest that the hydride shift product is likely racemic.8
Assuming racemic hydride shift product, it appears that direct
substitution chlorination product is formed as a near-racemic
mixture as measured by optical rotation.
However, exclusive retention of configuration in the product
was obtained with 2 equivalents of the Lewis acid at −78 °C.
These optimized conditions also suppressed inversion product
with trans-isomer 11; however, a significant degree of hydride
shift was also observed leading to cis-1-chloro-4-methylcyclo-
hexane (15) in nearly 1:1 ratio with the direct substitution
product. We did not observe products resulting from a hydride-
shift from the 2-positon (Table 3).
Importantly, in this 3-methylcyclohexanol system, we noted
that the cis-isomer led to cis-only chlorination product. Not
counting the hydride shift side reaction, we see that the trans-
isomer gives only the trans-direct substitution product. These
results do not seem to be consistent with a mechanism
involving either neighboring group participation or diaster-
eoselective attack on a carbocation as has been suggested for a
related system.12 If a classical SN1 mechanism were operative
Table 4. Chlorination Results with trans-4-Methylcyclohexanol (17) and cis-4-Methylcyclohexanol (18)
a
b
entry
ROH
conc (M)
temp (°C)
time (h)
TiCl4 (equiv)
13:14:15:16
yield (%)
1
17
17
17
17
17
17
17
18
18
18
18
18
18
18
0.50
1.0
0
0
0.50
0.50
2.0
0.10
0.10
2.0
1.0:1.0:1.4:5.4
1.0:1.0:1.4:5.4
1.0:1.0:1.4:5.4
2.0:1.0:2.5:13.7
2.0:1.0:2.5:13.7
5.0:1.0:8.5:49
1.0:0:2.0:15
74
83
73
72
80
76
78
61
62
64
61
65
60
62
2
3
1.0
−78
0
4
0.050
0.10
0.10
0.10
0.50
1.0
1.0
1.0
5
0
0.50
0.50
10
0.20
2.0
6
0
7
−78
0
2.0
8
0.50
0.50
2.0
0.10
0.10
1.0
9.3:1.0:6.0:1.4
9.3:1.0:6.0:1.4
5.6:1.1:6.8:1.0
5.6:1.1:6.8:1.0
6.3:1.0:8.2:1.3
64:1.5:62:1
9
0
10
11
12
13
14
0.050
0.10
0.10
0.10
1.0
0
0
1.0
0.20
2.0
0
0.50
2.0
−78
−78
2.0
8.0
2.0
62:1.6:58:1.0
a
b
Ratios determined by NMR. Isolated yields. Relatively low yields likely due to product volatility since NMR analysis of crude indicates near
quantitative conversion to the corresponding chloride.
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Table 5. Chlorination Results with (S)-2-Octanol15
Pyridine has been reported as an exception to the typical
behavior of nucleophilic solvents in the classical thionyl
chloride reaction. Inversion of configuration is obtained from
either the pyridinium chloride salt attacking from the backside
of the chlorosulfite or the exchange between the pyridine and
chloride of the chlorosulfite followed by the chlorine attacking
from the backside.17 We note that the reaction of l-menthol
with thionyl chloride in refluxing dichloromethane led to the
expected mixture of inversion and retention products in a ratio
of 1:3.9 with an overall yield 82%. By contrast, the present
methodology affords the menthyl chloride product with
complete retention of configuration in 93% yield (Scheme 1).
Schleyer and co-workers reinvestigated the Lewis and Boozer
hypotheses and offered a different mechanism based on frontier
orbital theory. He argued that the nucleophilic chlorine atom
was delivered from the chlorosulfite moiety via a 1,3-
sigmatropic shift.6c,18 In analyzing the possible shift geometries,
he noted that a suprafacial 1,3-shift is both geometrically and
symmetry allowed. Thus, a purely sigmatropic mechanism
should lead to chlorination products with inversion of
configuration without the intervention of nucleophilic solvents.
However, this is often not the case, and thus many have
concluded that the classical thionyl chloride reaction of alcohols
proceeds by the originally proposed SNi ionic mechanism.19
Others have invoked similar mechanisms, the so-called SNi
backside or SN2i.20 However, in the present reaction involving
the use of titanium tetrachloride, we have observed the
opposite outcome than that predicted by the Lewis and Boozer
mechanism; namely, predominantly retention products are
obtained even though a noncoordinating solvent (dichloro-
methane) was used. There appears to be another factor in play
with cyclic systems.
Hyperconjomer Theory. The work of Sorensen and co-
workers on methylcyclohexyl tertiary carbocations suggests that
these intermediates remain in a chair conformer (hyper-
conjomer) even after ionization.21 In the present work, we note
that whether the carbocation remains in the pyramidal
configuration or distorts to a planar geometry may be a key
factor in the stereochemical outcome of the reaction. Thus a
carbocation might be generated under relatively mild
conditions with the assistance of titanium tetrachloride.
Invoking a Sorensen-type intermediate which does not
transition to the planar geometry, we suggest that the cation
continues to maintain the pyramidal orbital ready to capture
the coming nucleophile from the less-hindered front face
(Scheme 3).
conc
(M)
time
(h)
TiCl4
yield
(%)
a
entry
1
(equiv)
[α]
20:(21 + 22)
1.0
0.50
12
0.20
2.0
−2.6
−3.5
+4.6
+4.4
+5.5
+5.7
−7.4
+4.3
1.2:1.0
1.0:1.0
90
77
83
83
87
93
51
60
b
2
1.0
3
4
5
6
7
8
0.10
0.10
0.10
0.10
0.050
0.050
1.0
1.0
1.0
1.0
24
1.0
0.80:1.0
0.80:1.0
0.80:1.0
0.80:1.0
3.3:1.0
5.0
10
20
0.20
1.0
20
0.90:1.0
a
Optical rotation of (R)-2-chlorooctane reported as −31.9 (4.5,
b
CHCl3). Reaction temperature was −78 °C.
Traditional Chlorination Mechanisms. Perhaps the most
salient feature of the present method is its limitation in
stereoselectivity to cyclic alcohols only. To better understand
this selectivity difference we first examine traditional ionic and
concerted mechanisms in the chlorination of secondary
alcohols with SOCl2. Lewis and Boozer extensively studied
chlorination reactions of alcohols with thionyl chloride.16 They
found that the configuration of the resulting chloride product
was dependent on both reaction temperature and solvent and
proposed a set of ionic mechanisms accounting for the different
reaction conditions. When a chlorination reaction involving
thionyl chloride and an alcohol is performed in a non-
coordinating solvent (e.g., toluene) or neat, ionization of the
chlorine−sulfur bond may occur (Scheme 2). However Lewis
and Boozer argue that the loss of sulfur dioxide must be
facilitated by the attack of chlorine ion from the back side of the
carbinol carbon by an SN2 mechanism.
Scheme 2. Lewis and Boozer Classic Mechanism for Alcohol
Chlorination with SOCl2
The Sorensen group put forward two carbocation isomers
with chair conformations, one isomer with a C−C bond
distorted to maximize Cβ−Cγ hyperconjugation. The other
conformer is stabilized through hyperconjugation by an
adjacent Cβ−Hax bond.22 These two “hyperconjomers” can
If a nucleophilic solvent such as dioxane is present, two
consecutive SN2 reactions take place leading to overall retention
of configuration. Other non-nucleophilic solvents provide a
solvating environment for the ionization of the chlorosulfite,
and thus dissociation into ion-pairs is no longer prohibitively
difficult. Depending on the polarity of the solvent involved,
cleavage may take place at the chlorine−sulfur bond or the
carbinol carbon−oxygen bond. Various pathways can then
result including a front side, backside attack, or a combination
of the two. As has often been observed, SN1-type mechanisms
are also possible leading to racemic chlorination of alcohols.16b
Scheme 3. Hyperconjomer Intermediates Leading to
Substitution Products
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interconvert; thus, a key aspect influencing stereoselectivity in
the present reaction would be the competition between the rate
of the hyperconjomer interconversion and the rate of their
nucleophilic capture.
involving stereoretentive Ritter reactions.8 Using DM, we
then characterized an initial set of transition state structures.
The obtained transition state conformations where then used as
a starting point to characterize these states with the saddle-
point-search module available with GAMESS. All calculations
were performed by employing DFT level of theory, using PBE
functional and the 6-31G** basis set (see the Experimental
Section for additional computational details).
Computational Analysis of Carbocation Geometry. As
described above, chlorination reactions of cis- and trans-3-
methylcyclohexanol with SO2Cl and TiCl4 gave direct
substitution products strongly favoring retention of config-
uration (Table 4). The trans-isomer seemed to be a simpler
system which, under optimal conditions, gave only 6% of a
single hydride shift byproduct. We thus chose this as a substrate
to computationally examine two possible reaction paths leading
to predominant retention of configuration (Figure 1a). In both
We hypothesize that our titanium-promoted reactions
involve chlorine from titanium capturing an empty orbital on
the carbocation center. We further argue that the reaction
proceeds via unique nonplanar carbocation mechanism in
which the ionized substrate retains memory of its original
configuration and is rapidly captured by a front side attack
leading to the observed stereoretention outcome. At least for a
brief instant, we suspect that the carbocation intermediate
remains “frozen” in its original configuration under the mild
conditions of its formation. As discussed in the next section,
our computational data appear to confirm this line of reasoning.
With sulfite-complexed TiCl4 as the source of nucleophilic
chlorine, an increase in the concentration of this Lewis acid
should increase the rate of complex formation and subsequent
cation capture at the expense of hyperconjomer interconversion
(leading to an increase in stereoselectivity). This mechanistic
interpretation is supported by our experimental studies
especially involving the chlorination of 3,3,5-trimethylcyclohex-
anol (7) and β-cholestanol (9) (Table 2) where exclusive
retentive product was obtained with added equivalents of
titanium(IV) chloride.
For those substrates where the low energy conformation
entails an hydroxyl group in an axial position, we observed a
greater degree of hydride shift products. Presumably, hydride-
shift (Wagner−Meerwein rearrangement) prefers hydride and
leaving group to assume an anticoplanar arrangement.23
Interestingly, both cis- and trans-3-methylcyclohexanols primar-
ily led to the same cis-hydride shift chlorination product 15
(Table 3). Perhaps in this case the competition between
nucleophilic capture and hydride-shift was somewhat equiv-
alent. For reasons not well understood, the carbocation centers
generated by the hydride shift appear to react with nucleophile
to give to same chlorination product with both trans- and cis-3-
methylcyclohexanol. A similar preference was observed for
trans-H-shift product (13) over the cis (14) in chlorination
reactions with cis- and trans-4-methylcyclohexanol (Table 4).
Computational Methods. Two different computational
approaches were used in the present investigation: (i) the
dimer method algorithm (DM)24−27 as implemented in the
CP2K package28 and (ii) the “standard” Hessian−Newton−
Raphson method29 as implemented in the GAMESS software
package.30 The DM method has been already described in
detail in the original work of Henkelman and Jon
́
sson.24 It is an
energy surface-walking method able to evaluate the local
curvature24,26 of a potential energy surface using two
symmetrically displaced atomic images of the system (the so-
called “dimer”). Therefore, the lowest curvature of the potential
energy surface, which corresponds to the lowest frequency
normal mode,31 is evaluated without the resource-intensive
calculation and diagonalization of the Hessian (i.e., second
derivatives of the potential energy). Due to its unique strategy,
DM represents a useful approach to find transition states in a
system involving a high number of degrees of freedom or a
large periodic system (e.g., inorganic surfaces) where the
numerical evaluation of the Hessian is computationally
demanding.25,27
Figure 1. (a) Initial best-guess structures used for the dimer method
(DM) calculation. (b) Transition-state geometries characterized using
the DM. Angles (in red) are given in degrees and distances in
Ångstroms (Å).
̈
hypotheses, the formation of the trans-3-methylcyclohexanoyl
carbocation intermediate is followed by a nucleophilic attack by
one chlorine atom. In one case, the attacking Cl originates from
the chlorosulfite group and the reaction follows path 1 (system
P1); in the other case, the Cl atom is provided by TiCl4 and the
reaction follows path 2 (system P2). Due to the high number of
internal degrees of freedom of the system, two conformational
In this work, we manually built a set of guess structures,
resembling a set of hypothetical transitions states guided by
chemical intuition based on our previously related work
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models (i.e., variant A and variant B) of each initial geometry
were analyzed, while maintaining the alcohol ring unchanged in
a chair conformation. Two transition states were characterized
by using DM for both the P1 reaction path (i.e., DM-TS1_A
and DM-TS1_B) and both the P2 reaction paths (i.e., DM-
TS2_A and DM-TS2_B) (Figure 1b).
By comparing the transition states reported in Figure 1b, it
was possible to recognize the main coordinates that define the
reaction paths. For reaction path P1, these key coordinates are
the distance between the “sulfinate oxygen” and the carbinol
Figure 2. Ring geometry of nonplanar 4-methylcyclohexane
carbocation. Angle θ1 is shown in red.
carbon atom of the trans-3-methylcyclohexanoyl moiety (RO−C
)
and the distance between the carbinol carbon and the chlorine
atom (R1C−Cl) of the sulfinate group. For the reaction path P2,
the key coordinate are the distance between the carbinol carbon
and one of the chlorine atoms of TiCl4 (R2C−Cl) and the RO−C
.
The transition state conformational models (i.e., A and B) of
each reaction path showed very small differences in the main
coordinates and, in all cases, these conformations showed
retention of configuration. The main coordinates defined above
did not differ more than 0.07 Å, demonstrating that transition
state variants of the same reaction path were essentially
equivalent. In general, for all transition states, the RO−C distance
was found to be shorter than either the R1C−Cl or the R2C−Cl
distances. These transition state geometries (Figure 1) are in
reasonable agreement with the simplified front side attack
models expounded in the work of Schreiner at the Hartree−
Fock level of theory.18b We note, however, that the comparison
of our results with those of Schreiner and co-workers is only
approximate since the systems examined by those authors were
significantly more simple (i.e., methyl chlorosulfite and ethyl
chlorosulfite) than those of the present study. Perhaps more
importantly, their system did not involve TiCl4 and the
calculations were performed at the Hartree−Fock level of
theory.
One of the key hypotheses in the present work is that
retention of configuration in the chlorination reaction is due to
a nonplanar carbocation that is captured by the nucleophile
while “frozen” in its original configuration. To computationally
examine this mechanistic assertion, we monitored the geo-
metrical values that define the conformation of the trans-3-
methylcyclohexyl structure in order to understand how these
putative nonplanar carbocations were stabilized.
The length of the Cβ−Cγ and Cβ−Hax bonds and the
carbocation out-of-plane angle (θ1) are reported in Table 6 (see
also Figures 2 and 3) for all transition states. In all cases, the
Cβ−Cγ bond lengths were stretched, the Cβ−Hax lengths were
approximately at the equilibrium values of 1.10 Å and the
angles θ1 spanned a range of values between 110° and 120°.
Our observed cyclohexyl geometry was consistent with a Cβ-Cγ
carbocation hyperconjomer as defined by Rauk and co-
Figure 3. DM and GM transition states. Angles are given in degrees
and distances in Å.
workers22,32 and by Alabugin.33 Combined with these previous
reports, our findings suggests that these chlorination reactions
proceed via the formation of a nonplanar carbocation species
stabilized, in this case, as a Cβ−Cγ hyperconjomer.
We next calculated energy levels with respect to structure
DM-TS1_B, the transition state of lowest energy (Table 6).
These energy differences did not exceed 4 kcal/mol; however,
there appears to be a preference for reaction path P1 (by 2
kcal/mol). All the transition state structures obtained from DM
calculations (DM-TS) were used as starting points to search for
the saddle point using the SADPOINT module of the
GAMESS updating the initial calculated Hessian matrix using
the mixed Murtagh−Sargent−Powell method.34 The obtained
structures were characterized as transition state by calculating
the proper number of imaginary harmonic vibrational
frequencies.
Table 6. Transition-State Energies Relative to DM-TS1_B
transition
states
Cβ−Cγ
Cβ−Hax
θ1
(deg)
relative energies
(kcal/mol)
(Å)
(Å)
DM-TS2_A
DM-TS1_A
DM-TS2_B
DM-TS1_B
1.593
1.599
1.594
1.600
1.592
1.592
1.595
1.597
1.100
1.102
1.099
1.101
1.099
1.100
1.099
1.100
113.4
111.5
117.4
111.1
3.9
1.9
2.2
0
The obtained DM transition states used as starting points
and those verified by the GAMESS protocol (GM-TS) are
shown in Figure 3 while the corresponding GM-TS geometrical
values are reported in Table 7. The DM-TS structures were
found to fit well with the GM transition state structures as
demonstrated by the corresponding geometrical values (Figure
3) that showed only minor differences. The root-mean-square
deviation (RMSD) of the GM transition states with respect to
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Table 7. Relative Energies with Respect to the GM-TS1_A/B
relative
RMSD Cβ−Cγ Cβ−Hax
energies
im freq
(cm−1
TS
GM-
TS2_A
(Å)
0.2
(Å)
(Å)
θ1
(kcal/mol)
)
1.594
1.595
1.593
1.599
1.596
1.595
1.594
1.599
1.099
1.099
1.099
1.101
1.099
1.100
1.099
1.100
113.7
2.5
0
168.96i
176.63i
170.37i
147.87i
GM-
0.17
0.08
0.07
112.7
113.1
112.7
TS1_A
GM-
2.3
0
TS2_B
GM-
TS1_B
the initial starting conformations (i.e., DM transition states)
were calculated as well (Table 7). These values are very small in
magnitude especially for both the transition states of variant B.
Based on the geometrical values shown in Figure 3 and in
Table 7, we argue that Cβ−Cγ bond lengths were maximized for
all the characterized GM transition states. The Cβ−Cγ length
values obtained for the GM transition states were very similar
to those obtained for the DM transition states. Both transition
state sets obtained from different protocol (i.e., GM-TS and
DM-TS) were thus compatible with the Cβ−Cγ hyperconjomer
confirming the “ionic nature” of the transition state in the
present chlorination reaction.
Figure 4. Reaction energy profiles including one reaction without
TiCl4 (transition state for the reaction with profile P0 is depicted in
Figure 5). All energies profiles are evaluated with respect to the
reactant energies.
We also calculated relative energy values with respect to the
lowest transition state energy associated to the GM-TS1_A/B
(Table 7). These values are in agreement with those described
above (Table 6). The differences among the transition state
energies did not exceed 3 kcal/mol and the preference for
reaction path P1 was further confirmed.
The transition states of the pathways P1 and P2 were
localized and validated by analysis of their imaginary vibrational
frequencies. Furthermore, the TS conformations were used as
starting point to relax the TS structures toward reactants and
products by performing an intrinsic reaction coordinate (IRC)
calculation with the IRC GAMESS module. This calculation is
used to track the lowest energy path that connects the TS to
the minimum conformation of the reactant and product
species.35
The energy profiles of the reactions as obtained by IRC
calculations were evaluated with respect to the local minimum
reactant conformations of each reaction (Figure 5). As
expected, the evaluated local energy minimums differed from
each other. However, these differences did not exceed 0.4 kcal/
mol; this difference is negligible compared to the relative
activation energies of the observed energy profiles (Figure 4).
Based on the activation energies calculated from these energy
profiles, it appears that reaction P1 is favored over reaction P2
by 3 kcal/mol (Figure 4).
The energy profile for a chlorination reaction was also
modeled without TiCl4 (black curve, Figure 4). The transition
state conformation for this metal-free reaction was also
modeled (Figure 5) and, as expected, the reaction path without
TiCl4 (P0) proceeded in a manner similar to reaction path P1.
Transition state P0 (TS0), however, was found to be
destabilized by 9 kcal/mol with respect to the TS1, and 6
kcal/mol with respect to TS2. We conclude this observed
destabilization is due to the absence of TiCl4. This computa-
tional result is not surprising given the observed catalytic effect
of TiCl4 in the present reaction.
Figure 5. Transition state for the chlorination reaction without TiCl4
(GM-TS0) was characterized with the saddle point search of
GAMESS. Distances are in Å.
compound and the OSO−TiCl4 complex. These products
were more stable than the reactants by 1 kcal/mol for both
reaction variants P1_A and P1_B. The TiCl4 did not take part
directly in the chlorination reaction, therefore it was in a relaxed
conformation and the titanium atom was in a “trans”
conformation with respect to the nucleophilic alcohol oxygen
of the sulfinate fragment. The trans-conformation minimized
the steric effects between TiCl4 and cyclic alcohol segment (see
Figures 1 and 2). In the P1 reaction, therefore, the TiCl4
promoted only the formation of the TS by stabilizing the
negative charge in the sulfinate fragment.
The P2 reaction proceeded from the reactants toward the
chlorinated compound and the Cl3Ti/OSOCl intermediate
compound. The reaction was completed by an additional
reaction step in which chlorine atom left the SO2Cl
intermediate to restore the TiCl4 catalyst. For variant reactions
A and B, the energy difference between the intermediate
products and the reactants was 3 kcal/mol in favor of reactants.
In the P2 reaction, TiCl4 was directly involved in the reaction
and titanium atom was in the “cis” conformation with respect to
the oxygen atom. The cis-conformation seemed to “chelate” the
carbocation minimizing the distance between carbocation and
the Cl atoms of the TiCl4 favoring nucleophilic attack. The P2
mechanism used the TiCl4 fragment to perform the
nucleophilic attack; therefore, it involved more degrees of
According to the just described computational results, the P1
reaction proceeded from reactants to give chlorinated
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freedom than the P1 mechanism. As a consequence, the P2
energy profiles showed a longer and more complex IRC than
the P1 energy profiles (see Figure 4). In particular, the P2_B
profile highlighted a sort of “hump” during the relaxation
toward reactants. Observing the IRC trajectory we realized that
this energy “hump” was due to a partial rotation of the TiCl4
along the Ti−O bond. By exploiting this degree of freedom the
system was able to place one of the Cl atom of the TiCl4
toward the carbocation, promoting the nucleophilic attack. The
presence of TiCl4 in the vicinity of the “frozen carbocation”
increased the probability of finding an atom of chlorine to
perform the nucleophilic attack, favoring the P2 reaction from a
statistical point of view
The interaction energy between the carbocation in the
present investigation (i.e., trans-4-methylcyclohexyl moiety)
and the fragment comprised of SO2Cl and TiCl4 were studied
using the localized molecular orbital-energy decomposition
analysis (LMO-EDA) implemented by Su and Li in the
GAMESS software36 for transition state structures of type A
(i.e., GM-TS2_A GM-TS1_A) and the structure of the reaction
modeled without TiCl4 (i.e., GM-TS0). We computed the
decomposition of the total interaction energy ΔEtot between
two fragments of each transition state into electrostatic
(ΔEelec), exchange (ΔEex), repulsion (ΔErep), polarization
(ΔEpol), and dispersion (ΔEdisp) components (Table 8).
Figure 6. HOMO/LUMO orbitals for GM-TS1_A and GM-TS2_A.
HOMO orbitals are depicted in red/blue, whereas LUMO are
depicted in green/yellow.
structures GM-TS1-A and GM-TS2_A (and that of other
related transition states) showed the characteristic Cβ−Cγ
hyperconjugation orbitals32 with the large p-orbitals localized
on the carbon atoms undergoing nucleophilic attack. As
expected, the molecular orbitals and those in all transition
states described in this work show no significant orbital overlap
between the HOMO and LUMO orbitals. This suggests the
present chlorination reaction is not likely to proceed by a
concerted (orbital controlled) pathway as suggested by the
previous LMO-EDA analysis.
Based on our computational results and experimental
findings, we put forward the following mechanism for the
TiCl4 catalyzed chlorination trans-4-methylcycohexanol and by
extension other cycloalkanols reported in this study. An alkyl
chlorosulfite generated in situ initially undergoes complexation
with the Lewis acid at the sulfoxyl oxygen (Scheme 4). This
Table 8. Decomposition of Interaction Energies (kcal/mol)
for Type A Transition States and for Transition State GM-
TS0 for the Reaction Modeled without TiCl4
TS
GM-
TS2_A
ΔEtot
ΔEelec
ΔEex
ΔErep
ΔEpol
ΔEdisp
−5.96
−79.67
−73.89
−4.68
27.16
−22.29
GM-
−82.6
−75.8
−4.14
−6.4
25.24
36.5
−21.17
−35.27
−6.7
TS1_A
GM-TS0
−105.69
−93.97
−6.55
Interaction energies were inversely proportional to the
relative ΔG* calculated in the present reaction (Figure 4).
The best interaction energy was observed with GM-TS0. In all
cases, the total interaction energies were dominated by the
electrostatic component (ΔEelec), suggesting that the inter-
action energies between the two fragments is mainly electro-
static. The relatively small values of ΔEpol suggest that
interactions between fragments are not covalent in nature.36
Moreover, using this computational technique, one can argue
that the differences between the GM-TS0 (without TiCl4) and
the other transition states modeled with TiCl4 rely mainly in
the ΔEelec component. This finding demonstrates that TiCl4
favors carbocation formation by stabilizing the negative charge
on SO2Cl and consequently decreases the activation energy of
the reaction.
Scheme 4. Proposed Mechanism for the Stereoretentive
Chlorination of Cyclohexanols
Finally, we sought to evaluate the possibility raised by
Schleyer and co-workers that reactions of chlorosulfites follow a
concerted mechanism.6c To this end, the highest occupied
molecular orbitals (HOMOs) and lowest unoccupied molecular
orbitals (LUMOs) of transition state structures GM-TS1_A
and GM-TS2_A were generated (Figure 6). The depicted
HOMOs (and that of other related transition states) showed
that the occupied molecular orbital were mainly localized in the
chlorine atoms capable of attacking the trans-3-methylcyclo-
hexanol carbocation and in the nucleophilic oxygen atom linked
to the cyclohexyl skeleton. The LUMOs for transition state
complex proceeds to form a nonplanar carbocation inter-
mediate that is stabilized though hyperconjugation. This
stabilization allows the carbocation to maintain its configuration
under the reaction conditions long enough to be captured by a
chloride ion delivered to the front side by the titanium(IV)−
OSOCl leaving group (Scheme 4). Computational evidence
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amounts) and stirred for the required time. The reaction mixture was
quenched with water, stirred until both layers were clear, and extracted
three times with dichloromethane. The collected organic extracts were
concentrated and the resulting oil was purified by silica gel
chromatography (usually using pure hexanes as eluent).
suggests that carbocation generation and its subsequent capture
by chloride do not occur as part of a concerted mechanism.
CONCLUSIONS
■
(1R, 2R)-1-Chloro-2-methylcyclohexane (racemic): 1H NMR (400
MHz, CDCl3) δ 3.53−3.47 (td, J = 10.59, 4.19 Hz, 1H), 2.25−2.17
(m, 1H), 1.83−1.74−1.71 (m, 2H), 1.68−1.54 (m, 4H),1.31−1.24 (m,
2H), 1.07(d, J = 6.47 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 67.7,
41.1, 37.5, 34.8, 26.5, 25.4, 20.2. Known compound.37
We have discovered an exciting modification of the well-known
and widely used alcohol chlorination reaction using thionyl
chloride. An important element of design in this new reaction
was the idea that chlorosulfites formed in situ could serve as
leaving groups capable of chelating the TiCl4 catalyst. The new
protocol leads to chlorination products in high yields under
milder conditions than the classical thionyl chloride reaction. In
most cases, these optimal results were obtained with catalytic
amounts of the Lewis acid. With chiral cyclic alcohols, the
reaction primarily yields products with retention of config-
uration raising mechanistic questions which we sought to
examine using computational methods. In this regard, two
different stereoretentive reaction mechanisms were investigated
using the dimer method as implemented in CP2K and the
SADPOINT module of the GAMESS. The transition-state
structures resulting from these approaches showed unambigu-
ously that both reaction pathways (i.e., P1 and P2) took place
through the formation of the Cβ-Cγ hyperconjomer. The
agreement between the results indirectly validated the DM
algorithm implemented in CP2K and showed that DM can be
efficiently used to characterize very difficult transition states.
The presence of TiCl4 in both cases stabilized the formation of
the carbocation providing evidence for the catalytic role of the
Lewis acid. Both pathways were compatible with a mechanism
in which the carbocation appears “frozen” in a nonplanar
geometry. The P2 reaction involved more degrees of freedom
than P1 reaction, with the TiCl4 providing a nucleophilic
chlorine atom in more ways than the SO2Cl alone. Because a
higher number of equivalent reaction paths of the kind P2 can
occur, an entropic contribution under experimental condition
likely offsets the observed difference in destabilization potential
energy relative to the P1 mechanism. Though proceeding
through a less favored transition state (3 kcal/mol) than that of
P1, we argue that the P2 pathway is favored in the “real reaction
environment”. Ultimately, this work puts forward a modified
conception of carbocation chemistry and a first practical
application of hyperconjomer theory. Further studies on this
system are currently underway especially with a view to
improving stereoselectivity and expanding substrate generality.
1
(1S, 3R)-1-chloro-3-methylcyclohexane (racemic): H NMR (400
MHz, CDCl3) δ 3.88−3.80 (tt, J = 11.69, 4.14 Hz, 1H), 2.19−2.14 (m,
2H), 1.82−1.75 (m, 1H), 1.66−1.61 (m, 1H),1.53−1.41 (m, 2H),
1.33−1.21 (m, 2H), 0.92 (d, J = 6.54 Hz, 3H), 0.90−0.80 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 59.7, 45.9, 36.9, 33.5, 33.1, 25.9, 22.2.
Known compound.38
(1R, 3R)-1-Chloro-3-methylcyclohexane (racemic): 1H NMR (400
MHz, CDCl3) δ 4.50−4.47 (b m, 1H), 1.99−1.89 (m, 3H), 1.82−1.65
(m, 3H), 1.57−1.52 (m, 1H),1.45−1.38 (m, 1H),0.99−0.93 (m, 1H),
0.89 (d, J = 6.53 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 60.1, 42.3,
34.1, 33.9, 26.4, 21.7, 20.2. Known compound.39
trans-1-Chloro-4-methylcyclohexane (racemic): 1H NMR (400
MHz, CDCl3) δ 3.85−3.77 (tt, J = 11.60, 4.19 Hz, 1H), 2.19−2.14 (m,
2H), 1.77−1.73 (m, 2H), 1.67−1.59 (m, 2H),1.44−1.35 (m, 1H),
1.06−0.96 (m, 2H), 0.87(d, J = 6.56 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 60.1, 37.1, 34.8, 31.2, 21.8. Known compound.39
cis-1-Chloro-4-methylcyclohexane (racemic): 1H NMR (400
MHz, CDCl3) δ 4.42−4.39 (b m, 1H), 1.98−1.93 (m, 2H), 1.81−
1.73 (m, 2H), 1.51−1.43(m, 5H), 0.93(d, J = 5.29 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 59.8 33.6, 28.9, 22.3, 14.0. Known compound.39
1
(1S, 5S)-1-chloro-3,3,5-trimethylcyclohexane (racemic): H NMR
(400 MHz, CDCl3) δ 4.07−3.99 (tt, J = 12.11, 4.19 Hz, 1H), 2.19−
2.13 (m, 1H), 1.91−1.86 (m, 1H), 1.70−1.61 (m, 1H), 1.36−1.31 (m,
2H), 1.18−1.09 (m, 1H), 0.95 (s, 3H), 0.91 (d, J = 6.51 Hz, 3H), 0.90
(s, 3H), 0.84−0.78 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 57.4,
49.5, 46.9, 45.7, 33.4, 32.8, 28.7, 25.1, 22.1.
Computational Details. Calculations were performed with the
CP2K/Quickstep40−42 and with GAMESS30 software packages. The
results were visualized with Molekel43 or VMD44 software packages.
All calculations were performed at the DFT level of theory using the
PBE functional45 and the 6-31G** basis set. CP2K calculations were
performed within the Gaussian-augmented-plane-wave (GAPW)42
framework and by using a density cutoff 280 Ry. Energies were tested
for convergence with respect to the wave function gradient of 10−6
hartree. All CP2K calculations were performed in vacuum without
periodic boundary conditions using Martyna−Tuckerman (MT)
Poisson solver.46 Molecular complexes were placed into the box
center. During calculations the molecular system dimension remain
within a box 11 × 6 × 6 Å. Accordingly with the Martyna−Tuckerman
specifications,46 a box of 24 × 15 × 15 Å was used to achieve a zero
electronic density at the edge of the box.
EXPERIMENTAL SECTION
■
To determine the transition states were used the dimer method24
implemented in CP2K and the SADPOINT module of the GAMESS
packages. The DM calculation in CP2K was activated specifying
DIMER as method in TRANSITION_STATE subsection of geo-
metrical optimization (GEO_OPT) section. The conjugate gradient
(CG) algorithm was used to minimize the angle rotation and to
translate the dimer. Based on our experience the dimer separation
value DR was set to 0.005 Å and the tolerance for rotational angle
convergence was set to 1.0 degrees. During optimization of the dimer
rotation the gradient was interpolated activating the INTERPOLA-
TE_GRADIENT Boolean keyword. Root mean square (RMS) values
of 0.0003 hartree/Bohr for force and 0.0003 Bohr for positions were
selected as convergence criteria.
The transition states calculated with GAMESS were fully optimized
with gradient convergence set to 0.0003 Hartree/Bohr. In the saddle
point searches, the Hessian was updated with the mixed Murtagh−
Sargent/Powell procedure.34 Imaginary frequencies and intrinsic
reaction coordinate calculations were used to verify the adjacent
local minima. The IRC were traced at the same level of theory and
General Procedure for Chlorination (High Concentration).
To an argon-blanketed and ice-cooled solution of alcohol (1.0 equiv)
in dichloromethane (1.0 M) was added thionyl chloride (1.5 equiv).
Hydrogen chloride, which is generated during this step, was vented
from the reaction. After 1 h, TiCl4 was added (catalytic to
stoichiometric amounts) and stirred for the required time (usually
15 min). The reaction mixture was quenched with water, stirred until
both layers were clear, and extracted three times with dichloro-
methane. The collected organic extracts were concentrated, and the
resulting oil was purified by silica gel chromatography (usually using
pure hexanes as eluent).
General Procedure for Diluted Chlorination Reactions. To an
ice-cold 1.0 M solution of alcohol in dichloromethane was added
thionyl chloride (1.5 equiv) and stirred for 1 h. Hydrogen chloride
which is generated during this step was vented from the reaction. The
reaction mixture was then diluted to the required concentration
(usually 0.5 or 0.01 M) by adding the required amount dichloro-
methane via syringe and cooled to the required temperature (usually
−78 or 0 °C). After 1 h, TiCl4 was added (catalytic to stoichiometric
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tolerance criteria from transition states toward both reactants and
(13) (a) Cozzi, P. G.; Benfatti, F. Angew. Chem., Int. Ed. 2010, 49,
256. (b) Muhlthau, F.; Stadler, D.; Goeppert, A.; Olah, G. A.; Prakash,
G. K. S.; Bach, T. J. Am. Chem. Soc. 2006, 128, 9668.
(14) Assuming pathway 2 (see the Computational Methods), the
relative energies (kcal/mol) of the transition states for these four
cyclohexyl isomers are as follows: cis-3-methyl (0), trans-4-methyl
(1.35), cis-4-methyl (2.02), and trans-3-methyl (2.13). See the
Supporting Information.
products directions using the Gonzalez−Schlegel algorithm.35
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of NMR spectra for entries in Tables 1 − 5 including
calculations of molar ratios of chlorinated isomers. Computa-
tional details and coordinates for the TSs obtained from the
DM and GM procedures. Movie showing the IRC trajectories
for reactions P2_B and P1_B (reported in Figure 5). This
material is available free of charge via the Internet at http://
pubs.acs.org.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: slepore@fau.edu, luca.bellucci_s3@unimore.it.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
L.B. thanks the Italian Institute of Technology (IIT) platform
Computation under the IIT seed project MOPROSURF as well
as Dr. Rosa Di Felice and Dr. Stefano Corni for useful
discussions. This work was partially supported by a grant from
the National Institute of Mental Health (MH087932).
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