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Journal of the American Chemical Society
within the diradical 18 to complete the formation of the carbo-
dienophiles. We used the classic approach of exposing a sub-
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stantial excess of each of the two competing reactants, in this
case 10 equiv each of two different dienophiles 13, with the
limiting reactant, here cyclopentadiene (14). Under the as-
sumption that the reaction is essentially irreversible, the prod-
uct ratio is a direct reflection of the relative rate constants for
the two competing DA reactions, because the initial relative
concentration of both dienophiles remains nearly constant
throughout the course of the reaction.
cyclic benzyne occurs with an extremely low activation barri-
er. Circumstantial evidence supports this view; we have never
observed a product from any HDDA cascade experiment that
suggests that diradical 18 is of any practical consequence. All
told, our experimental data validate the mechanistic pathway
laid out in Figure 3 for the HDDA cycloisomerization.
The dienophiles are listed in Table 2 in order of decreasing
reaction rate (red to blue). Note that the propynyl substituted
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b
compound 13f is the slowest of all and that the trifluoro-
methylated alkyne 13g is one of the fastest. The Hammett σp
and RSE parameters are also listed. The results are much bet-
ter aligned with the electron withdrawing nature of the substit-
uent, as expressed by σ , rather than with their radical stabiliz-
p
ing character, as reflected in the RSE values.
Table 2. Relative rates of Diels−Alder cycloadditions of
alkynes 13a-g with cyclopentadiene (14)
O
O
CDCl3
+
n-heptyl
Figure 3. The HDDA cycloisomerization (i.e., 16 to 17) proceeds
via diradical 18 rather than through a "concerted TS" geometry;
the relative rate data indicate that the "stepwise TS1" defines the
rate of reaction.
n-heptyl
rt or
90 °C
R
R
13a-g
14
15a-g
R
krela
σp
0.42
RSE
dienophile
ASSOCIATED CONTENT
Supporting Information
13e
13g
13d
CHO
CF3
47,000
16,800
2,100
840
−7.7
+1.9
−6.7
−4.9
−4.9
0.54
0.34
0.34
0.26
The Supporting Information is available free of charge on the
ACS Publications website.
COEt
13c
CO Me
2
New compound preparation, spectroscopic characterization data,
1
13
and copies of H and C NMR spectra (PDF).
1
3b
3a
CONMe
H
2
50
1
10
0
0
AUTHOR INFORMATION
1
3f
C
CMe
1
0.03
−12.1
Corresponding Author
a
1
Determined by H NMR analysis of pairwise competition reac-
* hoye@umn.edu
tions using two dienophiles (10 equiv each) and cyclopentadiene
in CDCl in a sealed vessel (see SI).
Notes
3
What have we learned from the HDDA reactivity of com-
pounds 7f and 7g vis-à-vis the rates of Diels−Alder cycloaddi-
tion of the ynones 13f and 13g? Indeed, it was the dichoto-
The authors declare to have no competing financial interests.
ACKNOWLEDGMENT
mous nature of the electron withdrawing (σ ) vs. the radical
p
This research was supported by the National Institutes of Health
(GM65597). NMR spectral data were collected with instrumenta-
tion acquired through the NIH Shared Instrumentation Grant pro-
gram (S10OD011952). T. W. received support from a Wayland E.
Noland Fellowship; T. W. and D. N. each received support from a
University of Minnesota Graduate School Doctoral Dissertation
Fellowship.
stabilizing effects (RSEs) of alkynyl vs. CF substituents (see
3
Table 1) that led us to include tetraynes 7f and 7g among the
HDDA substrates we studied. The results are quite definitive.
The tetrayne 7f, whose alkynyl substituent has the largest RSE
but only negligible electron withdrawing power, reacts the
fastest, and the trifluoromethylated alkyne 7g, with its non-
radical-stabilizing and strongly electron withdrawing CF sub-
3
stituent, the slowest (Table 1, red vs. blue, respectively) of all
the HDDA substrates we studied. This is clearly supportive of
a stepwise mechanism for the HDDA cycloisomerization reac-
tion, in which the substrate 16 proceeds via an initial (and
rate-determining) closure to the diradical intermediate 18 via
REFERENCES
(1) Baire, B.; Niu, D.; Willoughby, P. H.; Woods, B. P.; Hoye, T.
R. Nat. Protoc. 2013, 8, 501–508.
(
2) (a) Bradley, A. Z.; Johnson, R. P. J. Am. Chem. Soc. 1997, 119,
917–9918. (b) Miyawaki, K.; Suzuki, R.; Kawano, T.; Ueda, I. Tet-
9
"stepwise TS1" rather than proceeding directly to benzyne 17
via the "concerted TS" (Figure 3). This conclusion is in ac-
rahedron Lett. 1997, 38, 3943–3946. (c) Tsui, J. A.; Sterenberg, B. T.
Organometallics 2009, 28, 4906–4908.
(3) Wessig, P; Müller, G. Chem. Rev. 2008, 108, 2051–2063.
6
b,c,e
cordance with earlier computational analyses. Finally,
recall that those studies also indicated that recombination
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