Tactics for probing aryne reactivity: Mechanistic studies of silicon-oxygen bond cleavage during the trapping of (HDDA-generated) benzynes by silyl ethers

Article abstract of DOI:10.1039/c3sc53014k

We report mechanistic aspects of the trapping of thermally (HDDA) generated benzyne derivatives by pendant silyl ether groups, which results in net insertion of the pair of benzyne C_sp-hydribized carbon atoms into the silicon-oxygen sigma bond. Cross-over experiments using symmetrical, doubly labeled bis-silyl ether substrates established that the reaction is unimolecular in nature. Competition experiments involving either intramolecular or intermolecular dihydrogen transfer clock reactions (from within a TIPS isopropyl group or cyclooctane, respectively) vs. the silyl ether cyclization were used to gain additional insights. We evaluated effects of the steric bulk of the silyl ether trapping group and of the ring-size of the cyclic ether being formed (furan vs. pyran). These types of competition experiments allow the relative rates of various product-determining steps to be determined. This previously has only rarely been possible because aryne formation is typically rate-limiting, making it challenging to probe the kinetics of subsequent trapping reactions. Solvent effects (polarity of the medium) and computational studies were used to probe the question of stepwise vs. concerted pathways for the Si-O insertion.

Full text of DOI:10.1039/c3sc53014k

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Tactics for probing aryne reactivity: mechanistic
studies of silicon–oxygen bond cleavage during the
trapping of (HDDA-generated) benzynes by silyl
ethers†
Cite this: Chem. Sci., 2014, 5, 545
*
Thomas R. Hoye, Beeraiah Baire and Tao Wang
We report mechanistic aspects of the trapping of thermally (HDDA) generated benzyne derivatives by
pendant silyl ether groups, which results in net insertion of the pair of benzyne Csp-hydribized carbon
atoms into the silicon–oxygen sigma bond. Cross-over experiments using symmetrical, doubly labeled
bis-silyl ether substrates established that the reaction is unimolecular in nature. Competition experiments
involving either intramolecular or intermolecular dihydrogen transfer clock reactions (from within a TIPS
isopropyl group or cyclooctane, respectively) vs. the silyl ether cyclization were used to gain additional
insights. We evaluated effects of the steric bulk of the silyl ether trapping group and of the ring-size of
the cyclic ether being formed (furan vs. pyran). These types of competition experiments allow the
relative rates of various product-determining steps to be determined. This previously has only rarely
been possible because aryne formation is typically rate-limiting, making it challenging to probe the
kinetics of subsequent trapping reactions. Solvent effects (polarity of the medium) and computational
studies were used to probe the question of stepwise vs. concerted pathways for the Si–O insertion.
Received 30th October 2013
Accepted 2nd December 2013
DOI: 10.1039/c3sc53014k
www.rsc.org/chemicalscience
instances, interfere with the benzyne trapping reactions; and
(iii) a benecial consequence of point (ii) is that inherent
Introduction
reactivity of benzynes can sometimes be probed more funda-
mentally and/or that new types of aryne trapping reactions can
be uncovered.5,6 An example of this latter feature is the net
addition of a silyl ether (like that in 1) across the pair of strained
benzyne sp-hybridized carbons to give an o-(trialkylsilyl)aryl
We recently reported the mild, thermal polycyclization reaction
of triynes (cf. 1, Scheme 1) to give complex multi-ring benzenoid
products (cf. 2).1 We call this two-stage process an HDDA
cascade. The rst step involves generation of a reactive benzyne
derivative (cf. 3) by a net 4 + 2 cycloaddition event,2,3 which we
have termed a hexadehydro-Diels–Alder (HDDA) reaction.1 This
benzyne intermediate is then efficiently (and, in the reaction
type that is the subject of this paper, intramolecularly) trapped,
resulting in the expeditious construction of highly substituted
benzene derivatives (e.g., 2).
Among the hallmarks of this HDDA cascade are: (i) the
transformation of triynes like 1 to benzynes like 3 is computed
to be exothermic by ca. 50 kcal molꢀ1 (!)1 (cf. DErxn ¼ ꢀ51.4 kcal
molꢀ1 for the parent ethyne + 1,3-butadiyne to benzyne4); (ii)
this thermal mode of benzyne generation is complementary to
all previously reported, preparatively practical methods in two
important ways—the triyne precursors are not, themselves,
benzene derivatives and the aryne is formed in the absence of
reagents (e.g., bases or reducing agents) and byproducts (e.g.,
metal salts, amines, or halide ions) that can affect or, in some
Department of Chemistry, University of Minnesota, 207 Pleasant Street, SE,
Minneapolis, MN 55455, USA. E-mail: hoye@umn.edu
Scheme 1 The hexadehydro-Diels–Alder (HDDA) cascade of triyne 1
gives the highly substituted benzenoid derivative 2 via silyl ether
trapping of the HDDA-generated benzyne 3.
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c3sc53014k
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ether moiety (like that in 2). Such a process had been previously substrates smoothly underwent a HDDA cascade to provide the
unknown.1
corresponding tricyclic benzofuran derivatives 7a–c when
heated alone to the reux temperature of chloroform. The rate
of consumption of each substrate was virtually identical,
consistent with the fact that benzyne formation is the rate-
limiting step in these HDDA cascade processes. The slightly
lower yield of the TIPS-containing product 7c arises from a
competing dihydrogen disproportionation reaction that will be
discussed later.
With substrates 6a–c in hand, we designed several experi-
ments to address the question of molecularity of the trapping
reaction. First, to distinguish an intra-from an intermolecular
process, we carried out a simple crossover/competition study
using the pair of substrates 6b and 6c (Scheme 3, panel A).
When equimolar amounts of these were heated together in
chloroform, the only benzofuran derivatives observed were 7b
and 7c. Neither of the analogous products containing one each
of the TBS and TIPS groups (i.e., 7d and 7d0) was detected
(#0.5%) by LCMS analysis of the crude product mixture. This
result rules out a bimolecular process (i.e., the “second possi-
bility” presented above). A complementary crossover experi-
ment was also performed, this time using the mixed mono-TBS/
mono-TIPS silylated substrate 6d,12 which gave 7d and 7d0
(Scheme 3, panel B). Again, there was no evidence of bimole-
cularity (crossover); that is, none of 7b or 7c was seen by LCMS
analysis.
Results and discussion
To account for the trapping reaction that produces 2, we sug-
gested1 that the benzyne 3 is intercepted by the silyl ether
oxygen atom poised ve atoms away and that a transient zwit-
terionic species like 4 is generated. Migrations of silicon from
carbon to oxygen are well known in the form of the Brook
rearrangement.7 The opposite process, the reverse (or retro-)
Brook rearrangement (i.e., silicon migration from oxygen to
carbon), is less common but certainly precedented.8 These
reverse Brook reactions are most oen encountered within an
anionic manifold of intermediates. In a setting like that of 4 to
2, rearrangement would be expected to be particularly favorable
since zwitterionic character is quenched as a result of the silyl
group migration. A second possibility is that the reaction
mechanism involves zwitterion 4 but is not unimolecular. That
is, disproportionation of that intermediate with, e.g., another
copy of itself or with the silyl ether moiety in substrate 1 could
be responsible for formation of 2. A third possibility is that the
oxygen–silicon bond adds in concerted (and intramolecular)
fashion to the benzyne p-bond in 3, leading directly to 2. This
last possibility is of interest because concerted insertion into a
sigma bond with accompanying formation of two new sigma-
bonds (e.g., A–B + X]Y / A–X–Y–B in a single step) is a rare
type of transformation.
We then attempted to distinguish between the concerted vs.
stepwise mechanisms for silyl ether trapping (Scheme 1 bottom,
green vs. orange) by carrying out the reaction in several solvents
of varying polarity. In the stepwise mechanism either of the two
To probe these mechanistic issues, we prepared the set of
three symmetrical tetraynes 6a–c from the diol precursor 5
(Scheme 2). These differ only in the nature of the alkyl groups in
the trialkylsilyl moiety of their silyl ethers. Diol 5 was prepared
by Cadiot–Chodkiewicz cross-coupling reaction of the known
N,N-bispropargyl toluenesulfonamide9 with 4-bromo-3-butyn-1-
ol10 in the presence of catalytic CuCl in piperidine.1,11 Bis-sily-
lation of diol 5 gave each of the corresponding bis-TES, -TBS,
and -TIPS ethers 6a–c. As we anticipated, each of these
Scheme 2 Preparation of substrates 6a–c and the efficient HDDA
cyclization of each to benzofurans 7a–c.
Scheme 3 Crossover experiments establish unimolecularity.
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fundamental events could, in principle, be rate-limiting. The
rate constant for the rst step in that mechanism, formation of
the zwitterion 4 from benzyne 3 (cf. kS1, Scheme 1), would be
expected to be signicantly increased whereas that of the
second (kS2) decreased as the polarity of the medium is
increased.
To assess the impact of solvent polarity on the rate, it was
desirable to have a competitive trapping reaction that could be
used as a benchmark against which to clock the rate of silyl
ether trapping. Fortunately, one was at hand. The reaction of
bis-TIPS ether 6c gives a byproduct accompanying 7c—namely,
the isopropenyl-containing bicyclic arene compound 9 (Scheme
4, panel A). This arises by an intramolecular net redox process
in which two hydrogen atoms have been transferred, intramo-
lecularly, from a TIPS alkyl group to the aryne (cf. red arrows in
the benzyne intermediate 8). We have recently reported that this
type of unprecedented desaturation reaction is facile for
bimolecular H2-transfer reactions to benzynes from certain
cyclic hydrocarbons and that it proceeds by a concerted pathway
in which all six atoms involved in the bond-breaking and
-making events are essentially coplanar.6 Although the geometry
of the transition structure (TS) 8 might seem unusual at rst
glance, notice that the hydrogen atoms being transferred
occupy positions 9 and 11 of an array that can be mapped onto a
bicyclo[5.3.1]undecane skeleton. Indeed, we were able to locate
a computed TS geometry [M06-2X/6-31G(d)] for a variant of this
transformation in which the benzyne is minimally
substituted—namely, 8-TS (Scheme 4, panel B). Two hydrogen
atoms are each partially transferred from the isopropyl to the
benzyne sp-hybridized carbon atoms. Assuming that this
concerted mechanism is operative in 8, one would expect little
dependency on solvent polarity, rendering this competitive
transformation a good choice as an internal clock reaction.
Accordingly, we carried out the HDDA cyclization of the bis-
TIPS ether 6c in four solvents (Scheme 4, panel C), each of which
we have observed to be inert toward HDDA-generated benzynes.
These solvents range in relative permittivity (dielectric constant)
from 2.2–37.5 Debyes. As the polarity of the medium was
increased, we observed a steady increase in the branching ratio
(1H NMR analysis of the crude product mixture; cf. Scheme 4,
Scheme 4 Effect of solvent polarity on the silyl ether trapping using
an internal clock reaction. The ratio of intramolecular dihydrogen
transfer (6c to 9, panel A) to silyl ether trapping (6c to 7c) processes
shows
a dependence on solvent polarity (results tabulated in
panel C). DFT calculations on a truncated analog led to the identifi-
panel D) in favor of formation of the silyl ether trapped product cation of the concerted TS 8-TS (panel B, non-participating aliphatic
1
hydrogen atoms removed for clarity). H NMR spectrum of the crude
7c relative to the dihydrogen disproportionation product 9. We
interpret the direction of this trend as an argument against the
possibility that the rate-limiting event in the silyl ether trapping
product mixture from a typical experiment (panel D), this one for the
reaction performed in 1,2-dichloroethane, resulting in a 6 : 1 ratio of
products 7c : 9.
is the second step in the stepwise mechanism in Scheme 1 (i.e.,
that associated with the rate constant kS2). That event involves
conversion of a zwitterion (4) to a neutral structure (2) and, thus,
should be decelerated not accelerated in more polar solvents. process (3 to 2 and kC in Scheme 1) or for zwitterion formation
On the other hand, the magnitude of the observed rate (3 to 4 and kS1 in Scheme 1).
enhancement in a more polar solvent medium is small. Under
To gain more information relevant to the possibility of
the assumption that the rate of formation of the alkene 9 is the single-step insertion into the Si–O sigma bond, we also exam-
same in each solvent, the fastest to slowest krels for silyl ether ined this benzyne trapping process computationally. We
cleavage differ only by a factor of ca. 3. The small size of this studied each of the model benzyne-containing substrates I and
effect suggests only a minor degree of polarization in the tran- VI (Fig. 1, panels A and B, respectively). Each comprises a simple
sition structure for the rate-limiting step in the silyl ether trimethylsilyl ether and a mono-substituted benzyne, and the
trapping process. This is more consistent with an only modestly two differ only in the length of the methylene chain (two vs.
polarized and early TS, either for an asynchronous concerted three CH2s) linking the aryne and silyl ether moieties. Benzyne I
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implicit (or continuum) solvation model (solvation model
density, SMD13) during geometry optimization and, then, only
in the ve-membered series (cf. the pathway involving I–V). The
barrier heights leading away from that zwitterion (III) are quite
low, especially so in the forward direction, suggesting that it is a
eeting intermediate. Computational results (energies for I–VIII
and geometries for TSs II, IV, and VII) are given in Fig. 1. The
trends and conclusions are qualitatively the same regardless of
the nature of the basis set that was used.
The overall transformation for either trapping reaction (I to V
or VI to VIII) is highly exothermic (>50 kcal molꢀ1). The geom-
etry of each of the initial (and early) TSs II or VII shows only a
slight lengthening of the O–Si bond. The major difference in the
two (cf. TS geometries in Fig. 1) is seen in the dihedral bond
angle across the pair of benzyne carbon atoms and the silyl
ether oxygen and silicon atoms (:1234 ¼ 67ꢁ in II vs. 30ꢁ in VII).
TS II was able to settle into the zwitterionic intermediate III, in
which this dihedral angle has been signicantly reduced to 18ꢁ.
This then proceeds via the second TS IV (dihedral ¼ 13ꢁ) to
product V (dihedral ¼ 0ꢁ) via a second, low barrier and very
exothermic elementary step. The TS VII for the six-membered
substrate is very similar to III in both geometry and energy.
However, it directly evolves into benzopyran VIII (dihedral ¼ 0ꢁ)
without indication of encountering an intervening energy
minimum species (i.e., an analogous zwitterionic intermediate).
It is also of interest that the benzyne moiety in each of TSs II and
VII has undergone an appreciably large, induced distortion of
geometry in response to the approach of the oxygen nucleo-
phile. Specically, the two bond angles within the benzyne ring
at atoms C1 (:a12) vs. C2 (:12b) reveal a large distortion of the
benzyne in each (:12b ꢀ :a12 ¼ 31ꢁ for II and 26ꢁ for VII). This
induced distortion of the transition structure represents an
extrapolation of previous explanations of ground-state benzyne
distortions that effectively explain the site of greater electro-
philic character in unsymmetrical benzynes.14
We have also assessed the dependency of the relative rate of
intramolecular silyl ether trapping on the size of the silyl
substituent. A different type of dihydrogen transfer competition
`
experiment, this time vis-a-vis the external trapꢁping agent
cyclooctane,6 was used. Heating each of 6a–c to 65 C in cyclo-
octane led to a product mixture containing both 7a/b/c and the
reduced benzenoid product 10a/b/c (Scheme 5). The product
ratios reect the relative ease of trapping by the TES, TBS, and
TIPS silyl ethers, respectively, within the benzyne intermediates
11a–c. As expected, the least hindered TES is the fastest.
Specically, the TES ether traps the benzyne ca. 5ꢂ faster than
the TBS and 20ꢂ faster than the bulkiest, TIPS ether (cf. krels in
Scheme 5). The magnitude of this effect is consistent with a TS
for the product-determining step in which at least some degree
of interaction with the silicon center has been established.
Finally, we used the cyclooctane external competition
Fig. 1 Computed energies of minima and transition structures on the
potential energy surface for conversion of model benzynes I and VI
into silyl ether trapped products V and VIII (panels A and B, respec-
tively). Selected dihedral and internal bond angles are given for TSs II,
IV, and VII. [M06-2X/6-31G(d); enthalpic energies (kcal molꢀ1) are
given in panels A and B. Energies for each species using three basis sets
are given in panel C.
leads to the benzofuran product V, the homolog VI to the ben-
zopyran VIII. We used density functional theory (DFT) to map experiment to probe one additional feature—namely, the rela-
the reaction potential energy surface (PES) for each substrate/ tive ease of furan vs. pyran formation in the silyl ether trapping
product pair. The M06-2X functional was used for all calcula- event. Substrates 6b and 12 differ in the number of methylenes
tions and three different basis sets were used (see electronic (2 vs. 3, respectively) that tether the TBS ether to the alkyne
supplementary information†). We were able to locate a zwit- (Scheme 6).15 Each was heated in cyclooctane, and the ratio of
terionic species as an intermediate only when we applied an cyclization to reduction products (i.e., 7b to 10b vs. 13 to 14) was
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These types of competitive reactions allow one to probe the
relative rates of various product-determining steps in the reac-
tions of arynes. The rates of trapping reactions are oen diffi-
cult to unravel because aryne formation is typically rate-
limiting, making it challenging to probe the kinetics of the
subsequent events. The silyl ether trapping reaction shows a
modest rate enhancement in solvents of higher polarity, which
we interpret as evidence for only a moderate degree of polari-
zation in the transition structure for the rate-limiting step.
Larger alkyl groups on the silyl ether slow the rate of trapping
(ca. 20-fold between TES and TIPS). Precursors to benzofuran vs.
benzopyran products cyclize at essentially the same rate, sug-
gesting that enthalpic and entropic factors in these two types of
tethers are self-compensating. Based on the computational
results alone, one would conclude that the silyl ether trapping
event in the benzofuran class of precursors occurs in stepwise
fashion whereas the benzopyran homologs proceed via a
concerted Si–O insertion. However, given the small energetic
differences between these two pathways, this conclusion should
probably be viewed with a degree of caution. Computed TS
geometries suggest that the benzyne distorts in response to the
electronic character of the approaching nucleophilic silyl ether
oxygen atom. We speculate that this phenomenon may have
ramications extending to many other aryne trapping reactions.
Collectively, the studies reported here show how HDDA chem-
istry can provide access to new fundamental mechanistic
insights that are otherwise difficult if not impossible to obtain.
Scheme 5 Effect of steric bulk of the silyl group using an external
clock reaction. Competition of intramolecular silyl ether trapping vs.
bimolecular dihydrogen transfer from cyclooctane.
Scheme 6 Ring size effects. Competition of intramolecular silyl ether
trapping vs. bimolecular dihydrogen transfer from cyclooctane (the
external clock reaction).
Acknowledgements
This research was supported by the National Institute of
General Medical Sciences (GM65597) and the National Cancer
Institute (CA76497) of the U.S. Department of Health and
Human Services.
measured. The ratios turned out to be identical, suggesting a
compensating trade-off between entropic (favoring silyl ether
trapping enroute to the furan 7b) and enthalpic effects (lower
strain in the TS leading to pyran 13) for these two processes. It is
notable that the computed activation enthalpies (DH‡) for the
reactions passing through TSs II vs. VII (Fig. 1) are 3.1 vs. 1.8
kcal molꢀ1, respectively. The actual rate for each of these reac-
tions would also be, of course,16 dependent on the mole fraction
Notes and references
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2 K. Miyawaki, R. Suzuki, T. Kawano and I. Ueda, Tetrahedron
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`
of each of the reactive conformers I and VI vis-a-vis its associ-
ated family of all accessible conformations. The additional
rotatable bond in the latter substrate reduces the mole fraction
of VI (vs. that of I), thereby slowing its reaction rate to bring it
more in line with that of I than is implied by the computed DH‡
values alone.
3 A. Z. Bradley and R. P. Johnson, J. Am. Chem. Soc., 1997, 119,
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Conclusions
In summary, we have used various competition and crossover
experiments to gain mechanistic insights about the silicon–
oxygen bond cleavage event that attends trapping of HDDA-
generated benzynes containing a well-disposed, pendant silyl
ether. The process is unimolecular. Use of dihydrogen transfer
reactions, of both an intra- and intermolecular nature, was
instrumental to the design of the competition experiments.
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