Mechanism of electrophilic chlorination: Experimental determination of a geometrical requirement for chlorine transfer by the endocyclic restriction test

Article abstract of DOI:10.1021/ja0300463

An endocyclic restriction test for acid-catalyzed transfer of chlorine from a protonated chloroamine to an aromatic ring provides data that are consistent with a transition structure with a large bond angle between the entering and leaving groups around c

Full text of DOI:10.1021/ja0300463

Published on Web 05/23/2003
Mechanism of Electrophilic Chlorination: Experimental
Determination of a Geometrical Requirement for Chlorine
Transfer by the Endocyclic Restriction Test
Suk Joong Lee, Michael S. Terrazas, Daniel J. Pippel, and Peter Beak*
Contribution from the Department of Chemistry, UniVersity of Illinois at Urbana-Champaign,
Urbana, Illinois 61801
Received January 23, 2003; Revised Manuscript Received April 2, 2003; E-mail: beak@scs.uiuc.edu
Abstract: An endocyclic restriction test for acid-catalyzed transfer of chlorine from a protonated chloroamine
to an aromatic ring provides data that are consistent with a transition structure with a large bond angle
between the entering and leaving groups around chlorine. These results rule out a dissociative mechanism
or a mechanism that has an oblique angle between the entering and leaving groups.
Scheme 1
Reactions in which an electrophilic chlorine atom is trans-
ferred from a chlorinating agent to a nucleophilic substrate are
among the most widely used chemical processes. Applications
range from multitonnage scale for industrial applications to the
microscale in organic synthesis.
The limiting mechanisms for electrophilic chlorinations are
(1) a dissociative reaction, (2) a reaction through a trigonal
bipyramidal transition structure with the entering and leaving
groups at apical positions, or (3) a reaction through an
intermediate or transition structure that has an oblique angle
between the entering and leaving groups. These pathways,
Scheme 2
shown in Scheme 1 for the transfer of chlorine from a chlorine
carrier Cl-Y to a nucleophile Z, may be distinguished by
determining if there is a geometrical requirement for electro-
philic chlorine transfer.
The information available about the stereochemistry of
chlorine transfers is inferential. Paul and Haberfield interpreted
the acid-catalyzed rearrangement of N-chloroanilines to a
changing ratio of 2- and 4-substituted anilines and 2,4-
disubstituted anilines as evidence of an intermolecular process.1
Studies of the solid state by Parthasarathy, by Desiraju, and by
Pascal favor a large angle for chlorine electron donor interac-
tions.2 Pascal noted nitrogen-chlorine-carbon bond angles that
ranged from 166° to 180°.2c Boche and Cioslowski reported
calculations that reveal a large bond angle to be preferred
by Smith and co-workers provide a preference for an ionic
process over a radical pathway for this reaction.4
between methyl groups in the -ate complex transition structure
for the reaction of methyllithium with methyl chloride.3
The acid-catalyzed transfer of an electrophilic chlorine to
anisole by an N-chloroamine to give p-chloroaniline is a
representative chlorination. Kinetic and regiochemical studies
(1) Paul, D. F.; Haberfield, P. J. Org. Chem. 1976, 41, 3170-3175.
(2) (a) Ramasubbu, N.; Parthasarathy, R.; Murray-Rust, P. J. Am. Chem. Soc.
1986, 108, 4308-4314. (b) Pedireddi, V. R.; Reddy, D. S.; Goud, B. S.;
We have applied the endocyclic restriction test to a variant
Craig, D. C.; Rae, A. D.; Desiraju, G. R. J. Chem. Soc., Perkin Trans. 2
of the chlorination of anisole by connecting the electrophile and
the nucleophile as shown in Scheme 2 and using a reporter
molecule to evaluate molecularity.5,6 To compare the effect of
1994, 2353-2360. (c) Xu, K.; Ho, D. M.; Pascal, R. A., Jr. J. Am. Chem.
Soc. 1994, 116, 105-110.
(3) Boche, G.; Schimeczek, M.; Cioslowski, J.; Piskorz, P. Eur. J. Org. Chem.
1998, 1851-1860.
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J. AM. CHEM. SOC. 2003, 125, 7307-7312
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A R T I C L E S
Lee et al.
Table 1. Ratios of Chlorinated/Unchlorinated Compounds from
the Endocyclic Restriction Test with 1 and 2 Bearing the Short
Tether
Table 2. Ratios of Chlorinated/Unchlorinated Compounds from
the Endocyclic Restriction Test with 5 and 6 Bearing the Long
Tether
concna (M)
10/9
11/2
concna (M)
13/12
14/6
5.0 × 10-2
5.0 × 10-4
1.0 × 10-4
2.0 × 10-5
1.0
0.9
1.4
1.4
1.1
1.1
0.8
0.7
5.0 × 10-2
5.0 × 10-4
1.0 × 10-4
2.0 × 10-5
1.1
2.0
4.3
16
0.8
0.6
0.3
0.2
a Concentration is with respect to 1; an equimolar quantity of 2 is present.
a Concentration is with respect to 5; an equimolar quantity of 6 is present.
short and long tether connections between the reactive groups
on the intra- and/or intermolecularity of chlorine transfer,
compounds 1 and 5, which give 3 and 7, respectively, were
investigated. The tertiary amines 2 and 6, which have structures
very similar to those of 1 and 5, were used as reporter molecules
to track intermolecular chlorine transfer by the formations of 4
and 8, respectively. We are able to report experimental evidence
that is consistent with a transition structure for chlorine transfer
from a protonated chloroamine to an aromatic ring, which
requires a large bond angle between the entering and leaving
groups.
for the reactions of the short tethered substrates, 1 and 2, and
the long tethered substrates, 5 and 6, are shown in Tables 1
and 2, respectively.
These reactions consistently provided incomplete mass bal-
ances. The problem was compounded at the highest dilutions,
where reactions were executed with very small amounts of
reactants. To determine the extent to which materials were lost
during the postreaction sequence, we carried out a control
experiment in which known amounts of the initial reaction
products were taken through the aqueous workup and deriva-
tization procedure. Mixtures of 15 and 16 corresponding to 9
and 10 along with the tertiary amines 2 and 11, respectively,
and mixtures of 17 and 18 corresponding to 12 and 13 along
with the tertiary amines 6 and 14 were dissolved in trifluoro-
acetic acid to concentrations of 1.0 × 10-4 M and subjected to
the standard workup procedure to allow evaluation of the losses.7
The first experiment provided recoveries of 45 ( 2% of 9 and
10 and 86 ( 6% of 2 and 11, representative of the reaction of
1 and 2. The second experiment provided 44 ( 2% of 12 and
13 and 79 ( 2% of 6 and 14, representative of the reaction 5
and 6. These control experiments clearly indicate that the
secondary amines are grossly underrepresented in the final
isolated product mixtures. However, they also show that the
workup procedure does not systematically differentiate between
chlorinated and unchlorinated products within the carbamate
or tertiary amine series. The results of the control experiments
Results
The syntheses of the substrate and reporter molecules were
carried out as shown in Scheme 3.
The chlorinations were carried out with equimolar mixtures
of 1 with 2 and of 5 with 6 in trifluoroacetic acid/chloroform-d
at concentrations of the active chlorinating species of 5.0 ×
10-2, 5.0 × 10-4, 1.0 × 10-4, and 2.0 × 10-5 M. After reaction,
the mixtures were neutralized and treated with (Boc)2O to
convert the secondary amines present to carbamates. Chroma-
tography of the resulting four-component mixtures provided
separation of the carbamates from the tertiary amines, leaving
two-component mixtures. These two-component mixtures were
quantified by 1H NMR spectroscopy on the basis of comparisons
with authentic compounds. Directly determined compound ratios
(4) (a) Smith, J. R. L.; McKeer, L. C.; Taylor, J. M. J. Chem. Soc., Perkin
Trans. 2 1987, 1533-1537. (b) Smith, J. R. L.; McKeer, L. C.; Taylor, J.
M. J. Chem. Soc., Perkin Trans. 2 1988, 385-391. (c) Smith, J. R. L.;
McKeer, L. C.; Taylor, J. M. J. Chem. Soc., Perkin Trans. 2 1989, 1529-
1536.
(5) Beak, P. Acc. Chem. Res. 1992, 25, 215-222 and references therein.
(6) Preliminary studies on related reactions ruled out the use of a double-
labeling approach because of isotopic scrambling of the chlorinating
reactants. For an earlier study demonstrating the use of a reporter molecule
see: Anderson, D. R.; Woods, K. W.; Beak, P. Org. Lett. 1999, 1, 1415-
1417.
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Mechanism of Electrophilic Chlorination
A R T I C L E S
Scheme 3
were used to justify normalization of the raw product data as
shown in Tables 3 and 4. This normalization to quantitative
yields provides values that are useful for comparison to
simulated data (vide infra).
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A R T I C L E S
Lee et al.
Scheme 4
of greater than ∼15 members.5 In such a case, only an
intermolecular reaction would be observed for a substrate with
a short tether, whereas an intramolecular reaction could be
observed, at sufficient dilution to overcome the intermolecular
reaction, in a substrate with a long tether. If the transition
structure for atom transfer did not have a geometrical depen-
dence or was allowed with a small bond angle or if pseudoro-
tations could occur in an intermediate that allows entering and
leaving groups to be at an oblique angle, an intramolecular
reaction could be observed independent of tether length.5,8
Discussion
Under the endocyclic restriction test, comparison of molecu-
larities of atom transfer reactions for substrates that have
different length tethers between the groups donating and
accepting the transferred atoms can allow evaluation of a
geometrical requirement for the transfer.5 For example, if a
trigonal bipyramidal transition structure with a 180° bond angle
between apical entering and leaving groups is required for atom
transfer, that arrangement would not be readily achievable in a
ring of less than ∼12 members but could be achieved in a ring
(7) The workup would convert residual 1 or 5 to the secondary amine, 15 or
17, which would lead to 9 or 12, respectively.
(8) Tollefson, M. B.; Li, J. J.; Beak, P. J. Am. Chem. Soc. 1996, 118, 9052-
9061.
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Mechanism of Electrophilic Chlorination
A R T I C L E S
Table 3. Actual and Normalized Millimoles of Compounds from
the Endocyclic Restriction Test with 1 and 2
concna (M)
9b
10b
2b
11b
5.0 × 10-2 2.52 × 10-2 2.57 × 10-2 3.50 × 10-2 3.74 × 10-2
(3.7 × 10-2
)
(3.8 × 10-2
(3.7 × 10-2
(4.1 × 10-2
(0.8 × 10-2
)
(3.6 × 10-2
)
(3.9 × 10-2
)
5.0 × 10-4 1.77 × 10-2 1.68 × 10-2 3.43 × 10-2 3.60 × 10-2
(3.8 × 10-2
)
)
(3.7 × 10-2
)
(3.8 × 10-2
)
1.0 × 10-4 1.03 × 10-2 1.42 × 10-2 3.70 × 10-2 3.07 × 10-2
(2.9 × 10-2
)
)
(3.8 × 10-2
)
(3.2 × 10-2
)
2.0 × 10-5 0.34 × 10-2 0.46 × 10-2 0.74 × 10-2 0.52 × 10-2
(0.6 × 10-2
)
)
(0.8 × 10-2
)
(0.6 × 10-2
)
a Concentration is with respect to 1; an equimolar quantity of 2 is present.
b Normalized values to quantitative yields are shown in parentheses.
Table 4. Actual and Normalized Millimoles of Compounds from
the Endocyclic Restriction Test with 5 and 6
concna (M)
12b
13b
6b
14b
5.0 × 10-2 2.56 × 10-2 2.93 × 10-2 4.05 × 10-2 3.24 × 10-2
(3.5 × 10-2
)
(4.0 × 10-2
)
(4.2 × 10-2
)
(3.3 × 10-2
)
Figure 1. Simulated reaction progress curve for the reaction of 5 with 6
at 1.0 × 10-4 M.
5.0 × 10-4 1.50 × 10-2 2.96 × 10-2 4.54 × 10-2 2.45 × 10-2
(2.5 × 10-2
)
(5.0 × 10-2
(5.7 × 10-2
(1.3 × 10-2
)
(4.9 × 10-2
)
(2.6 × 10-2
)
1.0 × 10-4 0.55 × 10-2 2.35 × 10-2 5.31 × 10-2 1.38 × 10-2
Table 5. Comparison of Normalized Data and Simulated Results
in Model for the Endocyclic Restriction Test with 5 and 6
(1.3 × 10-2
)
)
(5.6 × 10-2
)
(1.4 × 10-2
)
2.0 × 10-5 0.02 × 10-2 0.33 × 10-2 1.00 × 10-2 0.16 × 10-2
concna (M)
12b
13b
13/12
(0.1 × 10-2
)
)
(1.2 × 10-2
)
(0.2 × 10-2
)
5.0 × 10-2
3.5 × 10-2
(3.7 × 10-2
2.5 × 10-2
(2.8 × 10-2
1.3 × 10-2
(1.3 × 10-2
0.1 × 10-2
(0.1 × 10-2
4.0 × 10-2
(3.8 × 10-2
5.0 × 10-2
(4.7 × 10-2
5.7 × 10-2
(5.7 × 10-2
1.3 × 10-2
(1.3 × 10-2
1.1
(1.0)
2.0
(1.7)
4.4
(4.4)
13
(13)
a Concentration is with respect to 5; an equimolar quantity of 6 is present.
)
)
)
)
)
)
)
)
5.0 × 10-4
1.0 × 10-4
2.0 × 10-5
b Normalized values to quantitative yields are shown in parentheses.
The reactions of 1 or 5 in the presence of equal amounts of
appropriate reporters, 2 or 6, respectively, allow analysis of the
molecularity of the chlorine transfer. If, hypothetically, only
intramolecular reactions occurred, 11 and 14 would not be
observed after the reaction. In the other limiting case, if only
intermolecular chlorine transfer occurred for equal amounts of
the substrate and reporter, four compounds, 9, 10, 2, and 11 or
12, 13, 6, and 14, respectively, would be present in equal
amounts after reaction. We report ratios of chlorinated/unchlo-
rinated for the analysis because they are independent of
differential losses of secondary and tertiary amines during
workup.
For the transfer of chlorine from 1, the ratios for 10/9 and
11/2 in Table 1 show the substrate and reporter to have
essentially the same values at each concentration. Such a result
is consistent with the substrate and reporter having the same
reactivities. This is the expected result if all chlorine transfers
from 1 are intermolecular.9
The compound ratios for the chlorine transfers from 5, shown
in Table 2 for 13/12 and 14/6, reveal that although the substrate
and the reporter exhibit similar reactivity at higher concentra-
tions, the compound ratios become significantly different at
lower concentrations. Qualitatively, the increasing ratio for 13/
12 versus the decreasing ratio for 14/6 is consistent with an
increasing intramolecular chlorine transfer for 5 at a decreasing
concentration of 5.10
concna (M)
6b
14b
14/6
5.0 × 10-2
4.2 × 10-2
(3.8 × 10-2
4.9 × 10-2
(4.7 × 10-2
5.6 × 10-2
(5.7 × 10-2
1.2 × 10-2
(1.3 × 10-2
3.3 × 10-2
(3.7 × 10-2
2.6 × 10-2
(2.8 × 10-2
1.4 × 10-2
(1.3 × 10-2
0.2 × 10-2
(0.1 × 10-2
1.3
(1.0)
1.9
(1.7)
4.0
(4.4)
6.0
(13)
)
)
)
)
)
)
)
)
5.0 × 10-4
1.0 × 10-4
2.0 × 10-5
a Simulated values in parentheses. b Concentration is with respect to 5;
an equimolar quantity of 6 is present.
that all of the intermolecular reactions would have the same
rate constant, reaction progress curves can be constructed
utilizing the simulation program KINSIM.11,12 For the short
tether case of 1 in the presence of 2, kintra was set equal to zero
and 1:1 ratios were predicted for 10:9 and 11:2 at all concentra-
tions as expected. This is in reasonable accord with the
experimental results. For the reaction of the long tether of 5 in
the presence of 6, an optimized relative rate constant of kinter
/
kintra ) 2000:1 was found to give a good fit to the data.10
A
specific reaction progress curve for the long-chain reaction at
1.0 × 10-4 is shown in Figure 1. In Table 5 the good agreement
between simulated compound ratios and those determined
experimentally is shown. This modeling shows that the different
profiles which are observed for these reactions are consistent
with an increasing intramolecular chlorine transfer for 5, the
substrate with long-chain tether on dilution.13
The possible intermolecular and intramolecular reactions for
the chlorination reactions of the substrates and reporters in
Scheme 2 are shown in Scheme 4. If the assumption is made
(9) The increasing ratios for both substrate and reporter with decreasing
concentration may reflect an indirect intermolecular component due to the
solvent acting as a chlorine carrier in a reaction that becomes more
significant as the rate of the direct intermolecular reaction is reduced by
the dilution.
The present results are consistent with a geometrical require-
ment for chlorine transfer in the chlorination of an anisole ring
(10) The values for the lowest concentration, although most indicative of the
different molecularities for the reactions of 5 and 6, were determined with
very small amounts of material and therefore subject to the greatest
quantitative error.
(11) Barshop, B. A.; Wrenn, R. F.; Frieden, C. Anal. Biochem. 1983, 130, 134-
145.
(12) http://www.biochem.wustl.edu/cflab/message.html.
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A R T I C L E S
Lee et al.
by a protonated chloroamine. These results rule out a dissocia-
tive mechanism whether envisioned as the actual formation of
“Cl+” or the more likely pathway of transfer of a chlorine to a
solvent or adventious nucleophilic carrier prior to product
formation.9 Also ruled out is an -ate complex that can undergo
chlorine transfer at an oblique angle or in pseudorotation in a
subsequent slow step.
for 19. This geometry is consistent with precedent for reaction
at bromine,14 with calculations,3 with the VSEPR model,5 and
with previous information.1,2,15
Acknowledgment. We are grateful to the National Science
Foundation (CHE 98-19422) and to the National Institutes of
Health (6M-18874) for support of this work.
This demonstration that a large angle is required between
the entering and leaving groups in an electrophilic chlorination
is consistent with reaction through a trigonal bipyramidal
transition structure as a transition state or intermediate as shown
Supporting Information Available: Experimental data for the
synthesis and characterization of 1, 2, 5, 6, and 9-14 and for
the results in Tables 1 and 2 are provided. This material is
available free of charge via the Internet at http://pubs.acs.org.
JA0300463
(13) Simulated values do not provide a perfect match to the experimental data.
We note both uncertainties in the exact amounts of products at the highest
dilutions and the possibility that an adventitous nucleophile or even
trifluoroacetic acid could act as a chlorine carrier.
(14) Allen, D. J.; Beak, P. J. Am. Chem. Soc. 1992, 114, 3420-3425.
(15) Zefirov, N. S.; Makhon’kov, D. I. Chem. ReV. 1982, 82, 615-624.
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