Thia-, Aza-, and selena[3.3.1]bicyclononane dichlorides: Rates vs internal nucleophile in anchimeric assistance

Article abstract of DOI:10.1021/jo102440k

Sulfur-, selenium-, and nitrogen-containing compounds bearing leaving groups in the β-position undergo facile substitution chemistry enabled by anchimeric assistance. Here we provide direct comparisons between such systems in the rigid bicyclo[3.3.1]nonane framework easily derived from 1,5-cyclooctadiene. For a series of dichloride electrophiles of this type, the relative reactivities were found to be Se ? (alkyl)N > S ≥ (propargyl)N > (phenyl)N, with the reaction rates at the two extremes differing by more than 3 orders of magnitude. For the N-alkyl case, substitution rates were largely independent of the trapping nucleophile but were strongly dependent on solvent, showing that the process is controlled by the formation of the high-energy three-membered cationic intermediate.

Full text of DOI:10.1021/jo102440k

ARTICLE
pubs.acs.org/joc
Thia-, Aza-, and Selena[3.3.1]bicyclononane Dichlorides:
Rates vs Internal Nucleophile in Anchimeric Assistance
Adrian A. Accurso,† So-Hye Cho,† Asmarah Amin,† Vladimir A. Potapov,‡ Svetlana V. Amosova,‡
and M. G. Finn*,†
†Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines
Road, La Jolla, California 92037, United States
‡A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Division of the Russian Academy of Sciences, 1 Favorsky Street, 664033 Irkutsk,
Russian Federation
S Supporting Information
b
ABSTRACT: Sulfur-, selenium-, and nitrogen-containing compounds bearing leaving
groups in the β-position undergo facile substitution chemistry enabled by anchimeric
assistance. Here we provide direct comparisons between such systems in the rigid
bicyclo[3.3.1]nonane framework easily derived from 1,5-cyclooctadiene. For a series of
dichloride electrophiles of this type, the relative reactivities were found to be Se .
(alkyl)N > S g (propargyl)N > (phenyl)N, with the reaction rates at the two extremes
differing by more than 3 orders of magnitude. For the N-alkyl case, substitution rates were largely independent of the trapping
nucleophile but were strongly dependent on solvent, showing that the process is controlled by the formation of the high-energy
three-membered cationic intermediate.
’ INTRODUCTION
the homoanomeric effect in the case of a β-disposition between
interacting groups).9 Since we are interested in a variety of
applications of this potential “click” reaction,10 we wished to
survey analogues containing three of the most active internal
nucleophilic centers—nitrogen, sulfur, and selenium—in order
to learn what range of reactivities might be accessible.
The transannular addition of sulfur dichloride to cis,cis-1,5-cyclooc-
tadiene (1,5-COD) gives the 9-thiabicyclo[3.3.1]dichloride 1,
as shown in Figure 1A. This process was first reported in 1966
independently by Weil (Hooker Chemical Co.),1 Corey
(Harvard Univeristy),2 and Lautenschlaeger (Dunlop Corp.),3
listed in order of submission dates of their respective papers,
inaugurating or continuing work in all three groups on substitu-
tion chemistry by anchimeric assistance. In recognition of these
seminal contributions, we designate such 1,5-COD-derived
species bearing a donor atom in the 9-position and leaving
groups β to the donor as “WCL” electrophiles.
Polymer cross-linking by sulfenium ion reactions with CdC
double bonds is one of the key mechanisms for the vulcanization
of rubber.4 Each of the pioneering WCL investigators noted that
similar reactions of SCl2 with other cyclic dienes gave polymeric
products unless conducted at high dilution but that the cyclooc-
tadiene-derived material did not. The resistance of 1,5-COD to
polymerization is due to the favorable torsional properties of the
dual-chair bicyclo[3.3.1] skeleton, which is one vertex and two
bonds short of an adamantyl framework.5 While the facile
substitution chemistry of this species was noted by all of the
pioneers, its scope and limitations were not explored.
’ RESULTS AND DISCUSSION
Selenium dichloride and dibromide can be generated from
elemental selenium and sulfuryl chloride or bromine in
chloroform.11 When freshly prepared they are practically pure
compounds which can be used for the synthesis of organosele-
nium adducts.11 Thus, the addition of SeCl2 to 1,5-COD was
found to proceed smoothly in chloroform to furnish adduct 2 in
>95% yield more rapidly than the analogous sulfur reaction
(Figure 1A). Compound 2 was previously prepared from Se2Cl2
and 1,5-COD by Lautenschlaeger12 but was not characterized.
Nitrogen analogues 3 were synthesized by a stepwise procedure
that is more general than a previously reported route using N-
halosuccinimide.13 Catalytic oxidation14 of 1,5-COD to cis-diepoxide
4 was followed by ring-opening with four different amines to provide
9-azabicyclo[3.3.1]- and [4.2.1]nonanediols 5aÀd (Figure 1B).
Heating each mixture with thionyl or methanesulfonyl chloride
provided the 9-azabicyclo[3.3.1]nonane dichlorides 3aÀd as the
hydrochloride salts.
We have previously described the highly reliable bond-form-
ing ability of sulfur WCL electrophiles with heteroatom6 and
Grignard nucleophiles7 and their reversibility when the nucleo-
phile also constitutes a good leaving group, such as halide,
isothiocyanate, and most importantly, tertiary or heterocyclic
amine.6a,8 The WCL motif also constitutes a conformationally
constrained and therefore well-controlled test bed for the
fundamental study of anchimeric assistance (closely related to
The formation of the most stable bicyclo[3.3.1]nonane isomer
in each case shows that reversible addition/elimination of
chloride occurs for sulfur, selenium, and both aliphatic and
Received: December 10, 2010
Published: May 05, 2011
r
2011 American Chemical Society
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|

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Figure 1. (A) Synthesis of sulfur and selenium dichloride electrophiles 1 and 2. (B) Synthesis of aza analogues 3aÀd. Compound 3a was isolated as a
91:9 mixture of [3.3.1] and [4.2.1] isomers, the only dichloride to show such a distribution (Supporting Information).
Table 1. Observed First-Order Rate Constants for the
Substitution Reactions Shown in eq 1
aromatic amine congeners. The involvement of anchimeric assistance
throughout the series is similarly indicated by the substitution
chemistry of each of its members, which occurs with retention and
is dependent on the presence of an atom with active lone pairs in the
bridging position,6a but no comparison of the relative reactivities of
these WCL electrophiles has been described.
d
entry
elec (Z)a
nucb
kobsc (minÀ1
)
krel
t1/2 (min)
solvent = acetonitrile
1
2
3
4
5
1 (S)
BnNH2 1.45 ( 0.02 Â 10À2 112 47.7 ( 0.5
1
A pilot study by H NMR determined that the sulfur dichloride
2 (Se)
BnNH2 not measured
fast not measured
electrophile 1 was at least 15 times more reactive with benzylamine
than the aniline derivative 3a and that the disubstituted products (eq 1)
were exclusively formed in both cases (data not shown). However, the
NMR method was too cumbersome for the determination of absolute
rates. Instead, the reactions were analyzed by following the disappear-
ance of each electrophile using quantitative GCÀMS in the presence of
excess benzylamine and an internal standard, in either dry acetonitrile
or dry THF. Alcohol or water additives were avoided in order to
eliminate the possibility of solvolysis rather than substitution by the
desired amine nucleophile. The disubstituted products precipitated
under these conditions and were therefore not analyzed during the
kinetics experiments, but were confirmed as the predominant products
(>90% yield) by independent reactions on a larger scale. The only ex-
ceptions were adducts of 2, which were prone to decomposition upon
storage and chromatography. Intermediate monosubstitution products
were not detected by GCÀMS, suggesting that the second substitution
reaction goes faster than the first, but their absence has not been
rigorously established other than for the sulfur electrophile (1),6a and
other reports have shown the opposite trend.15 For the desired purpose
—determining the influence of the central heteroatom nucleophile on
reactivity—we therefore followed the disappearance of the starting
dichlorides as the simplest possible comparison applicable to all cases.
3a (NPh)
BnNH2 1.30 ( 0.04 Â 10À4 1c 5320 ( 140
3b (N-n-heptyl) BnNH2 1.15 ( 0.02 Â 10À1 881 6.0 ( 0.1
3c (N-propargyl) BnNH2 3.27 ( 0.11 Â 10À3 25 212 ( 7
solvent = THF
6
7
8
9
1 (S)
BnNH2 1.52 ( 0.10 Â 10À4 1c
4550 ( 310
2 (Se)
BnNH2 6.39 ( 0.15 Â 10À3 42 109 ( 3
3a (NPh)
BnNH2 not measured
slow not measured
3b (N-n-heptyl) BnNH2 9.32 ( 0.71 Â 10À4
6
2
744 ( 60
10 3c (N-propargyl) BnNH2 3.56 ( 0.18 Â 10À4
1950 ( 100
solvent = 2:1 THF:H2O
11 3d (NBn) C3H7N
12 3d (NBn) NaN3
13 3d (NBn) NaCN
14 3d (NBn) pyridine
3.51 ( 0.36 Â 10À2 1.3 19.8 ( 2
6.31 ( 0.41 Â 10À2 2.4 11.0 ( 0.7
3.35 ( 0.11 Â 10À2 1.3 20.7 ( 0.7
2.66 ( 0.18 Â 10À2 1c
26.0 ( 1.8
15 3d (NBn) phenoxide 6.13 ( 0.14 Â 10À2 2.3 11.3 ( 0.3
a WCL electrophile; the bridging group at the 9-position is shown in
parentheses. b Capturing nucleophile used in 15-fold excess concentra-
tion relative to electrophile. c Rate constants for each entry are reported
as the average of three separate experiments with the indicated standard
d
deviations. krel is designated as 1.0 for the slowest rate constant
observed in each solvent system.
The reactions were performed under pseudo-first-order con-
ditions, giving the observed rate constants shown in Table 1. The
substitution reaction of selenium WCL electrophile 2 was too
fast to measure in acetonitrile, being largely complete before the
first aliquot could be taken. The remaining four electrophiles were
found to exhibit relative reactivities in the order 3b > 1 > 3c > 3a.
The nature of the 9-aza substituent therefore contributes sub-
stantially to the reaction rate in the expected order of nucleo-
philicity, N-heptyl > N-propargyl > N-phenyl, with a difference in
rate of more than 800-fold between the slowest and fastest cases.
In order to measure the reaction rate of 2, the experiments were
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Figure 2. Mechanism of anchimeric assistance for compounds of the WCL class.
performed in THF under otherwise identical conditions,
slowing the reactions by providing a less polar environment.
The order of reactivity was almost the same as in acetonitrile
(2 > 3b > 3c > 1 > 3a), but in this case 3c was observed to be
slightly faster than 1. The selenium WCL compound 2 was
approximately seven times more reactive than its next closest
competitor, heptylamine-bridged 3b.
conditions used (50 mM electrophile, large excess of nucleo-
phile) but are dominated by the first-order pathway. When
trapping nucleophile is omitted in aqueous THF, the reactions
are much slower, showing that the kÀ1 step is competitive with
trapping by water.
The observed solvent effects are also consistent with rate-
determining internal displacement of chloride, with reactions in
acetonitrile and aqueous THF being much faster than in THF
alone. Thus, the reactions of benzylamine with 1 and 3b are
approximately 90 and 120 times faster, respectively, in acetoni-
trile (Table 1, entry 1 vs 6 and 4 vs 9). N-Propargyl electrophile
3c reacts only nine times faster in acetonitrile than in THF, for
reasons that we cannot yet explain, and the selenium- and aniline-
based reagents 2 and 3a could not be quantitatively compared
but also react much faster in acetonitrile. This solvent is more
polar and better able to solvate chloride ion, both factors favoring
formation of the electrophilic intermediate.17 The order of
effectiveness of the internal nucleophile (Se > heptylamine > S g
propargylamine > aniline) suggests that a combination of
factors are at work, including ability to stabilize a positive charge
(Se > S > N) and basicity (N-alkyl > N-aryl).
To the comparisons between internal nucleophiles that have
appeared previously (for example, sulfur vs selenium,16 oxygen vs
nitrogen,18 and halogen vs oxygen vs nitrogen vs sulfur19), the
results reported here add the first quantitative comparison of the
activating abilities of nitrogen, sulfur, and selenium atoms in an
otherwise identical and well-defined anchimeric assistance pro-
cess. The rate differences are substantial, amounting to more
than a factor of 1000. This allows us to tune reactivity in a
predictable way for linkage formation and destruction, providing
a versatile tool for the synthesis of functional small molecules and
polymers.
The effect of nucleophile identity was examined by comparing
the rates of chloride substitution with five different nucleophiles
(eq 2), using benzylamine-bridged hydrochloride salt 3d as a
representative WCL electrophile that is easily detected by UVÀ
vis spectroscopy and reacts with similar rates to 3c (data not
shown). To ensure that compound 3d existed primarily as the
free base during the kinetic study, 5 equiv of triethylamine was
added to the mixture at the beginning of each experiment. These
reactions were performed in a 2:1 THF/water mixture in order to
provide a common medium that dissolves all of the nucleophiles,
giving rise to substantially faster substitution than under non-
aqueous conditions, presumably because of enhanced support
for the formation of the high-energy charged aziridinium inter-
mediate. Accordingly, initial concentrations were reduced 10-
fold to slow the overall process to an easily measurable time
frame. Ionic strength was equalized by the addition of NaPF6 to
the reactions of the uncharged nucleophiles (propylamine and
pyridine; see the Experimental Section). Rates were again
observed by following the disappearance of starting material,
this time by HPLC. Entries 11À15 of Table 1 show that the
process is largely insensitive to the nature of the differing
nucleophiles, which are expected to be of very different
activity.
The above data are consistent with a two-step mechanism
involving reversible formation of a cationic intermediate followed
by interception of this species with a nucleophile as shown in
Figure 2. We draw the key intermediate as a three-membered ring
(aziridinium, episulfonium, or episelenenium; structure 6) be-
cause of the very strong preference for stereochemical retention
exhibited by all of these substitution reactions, but it is also
possible that hyperconjugative stabilization of the carbon-cen-
tered cation takes place.16 In either event, when nucleophilic
trapping of is much faster than its formation (k2[Nuc] . kÀ1),
the reaction will appear to be first order with rate-limiting
formation of the strained intermediate. If, however, concentra-
tions are lowered so that the bimolecular capture rate is slowed
(in the extreme, k2[Nuc] , kÀ1), then the reaction should have
second-order character. The observed rates did vary as a function
of capturing nucleophile (Table 1, entries 11À15; a factor of 2.4
overall), but to a much smaller degree than as a function of the
internal nucleophile (Table 1, entries 1À5 and 6À10; factors of
hundreds to about 1000). This suggests that the reactions may
have a small amount of second-order character under the
’ EXPERIMENTAL SECTION
Compound 1 was prepared as previously described.6b The selenium
analogue 2 was prepared by reaction of SeCl2 with 1,5-cyclooctadiene,
and the amine WCL electrophiles 3 were prepared from cis-1,5-
cyclooctadiene diepoxide as outlined above. These procedures and
characterization data are provided in the Supporting Information.
Kinetics experiments as a function of electrophile (Table 1, entries
1À10) were performed at room temperature on 50 mM solutions of
each dichloride in dry THF or acetonitrile containing an internal
standard. Similar kinetics measurements were performed at room
temperature as a function of nucleophile (Table 1, entries 11À15) on
2:1 THF/water solutions of 3d (5 mM), NEt3 (25 mM, 5.0 equiv.), an
internal standard, and added NaPF6 to equalize ionic strength when
necessary. The reactions were initiated by the addition of 15 equiv of
nucleophile to the rapidly stirred solutions and were followed by GC or
HPLC analysis of aliquots removed and quenched at certain times.
Experimental details are provided in the Supporting Information.
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’ ASSOCIATED CONTENT
S
Supporting Information. Details of syntheses, com-
b
pound characterization, kinetics procedures, and representative
kinetics plots for results shown in Table 1. This material is
available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: mgfinn@scripps.edu.
’ ACKNOWLEDGMENT
We thank the Skaggs Institute for Chemical Biology, the
National Science Foundation (1011796), and the Russian Acad-
emy of Sciences (Program 5.1.8) for support of this work. We are
grateful to Dr. David Díaz and Dr. Bunpei Hatano of the
Sharpless laboratory for early syntheses of compounds 1 and
3b, to Dr. Andrew Vaino for early experiments along these lines,
and to Dr. Laura Pasternack for helpful expertise in NMR
spectroscopy.
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