Norbornene Reactivity
COMMUNICATION
reduces the reaction kinetics. In contrast, all derivatives with
electron-pushing substituents, such as the alcohols 3, 4, 6,
and 8 are 3–4 times faster. Interestingly, the rate accelera-
tion is very high in the exo-tricyclo[3.2.1.02,4]oct-6-ene-3-
methanol 12. In this case, the corresponding alcohol reacted
about 10 times faster than the ethyl ester 11. Because 11 is
significantly slower than the exo compounds 1 and 3, again
increased ring strain does not account for the higher reactiv-
ity of 12. These results show that additional strain does not
increase the reactivity, which is quite surprising. We noted,
however, a substantial reactivity difference between the exo
and the corresponding endo norbornene isomers. The large
reactivity difference was consistently observed in all exam-
ined compounds. The endo compounds all react significantly
less efficiently. This is particularly impressive for compound
10. The five-membered ring does not add strain and togeth-
er with the endo-configuration a compound is obtained,
which has a strongly reduced reactivity of only k=(0.05Æ
0.002)mÀ1 sÀ1. Comparing the rate constants of compound 1
with 2 and that of compound 3 with 4, an approximately 2.5
fold increase in favor of the exo isomer was observed. When
we performed the measurements of the two most reactive
derivatives 3 and 12 at 378C, the observed rate constants
were k=(8.0Æ0.46)mÀ1 sÀ1 and k=(6.1Æ0.17)mÀ1 sÀ1, re-
spectively, manifesting the potential of these derivatives.
Compound 12 has the additional advantage that it contains
a mirror symmetry element (Cs symmetry) so that upon re-
action only two defined products are formed. The high sym-
metry of compound 12 together with its superior reactivity
makes it the preferred choice for reverse electron-demand
Diels–Alder reactions (see Figure S1 in Supporting Informa-
tion).
Figure 2. M062X/6-311+GACTHNUTRGNE(UNG d,p)-optimized transition-state structures for
the inverse electron-demand Diels–Alder reaction of tertrazine with exo-
norbornene 3 (a) and with endo-norbornene 4 (b), both leading to the
exo-addition of tertrazine. The barrier for the reaction of 3 with tetrazine
is 0.65 kcalmolÀ1 lower than the analogous reaction of 4. The indicated
À
H1 O hydrogen bond (2.66 ꢂ) of 3 is shorter than the corresponding
À
H2 O hydrogen bond (2.85 ꢂ) of 4.
state for 3 with respect to 4 is the stronger hydrogen bond
À
between H1 and the oxygen atom compared to the H2 O
hydrogen bond of 4[40] (Figure 2). This phenomenon was al-
ready observed in gas-phase calculations. Further stabiliza-
tion of the transition state towards 3 occurs due to the inter-
action of its stronger dipole moment with the solvent water
(see the Supporting Information).
In conclusion, we performed a short systematic kinetic
study about the reactivity of norbornene derivatives in in-
verse electron-demand Diels–Alder reactions with tetra-
zines. We experimentally evaluated the influence of various
substituents and of the whole geometry of the norbornene
on the reaction rates. The observed data clearly show that
norbornenes bearing non-electron-withdrawing substituents
in the exo position are most favored in the reaction. We per-
formed a computational analysis of the transition states of
the DARinv of tetrazine with exo and endo norbornene de-
rivatives to rationalize the observed rate difference. The cal-
culations show an excellent agreement with the experimen-
tal data and support the observed higher reactivity of the
exo isomers. We finally conclude that for biomolecular label-
ing studies one should consider compounds 3 and 12. The
former derivative is synthetically easily available in multi-
gram quantities, while the symmetry of compound 12 make
this compound the preferred dienophile in inverse electron-
demand Diels–Alder reactions with, for example, tetrazines,
particularly in cases where a high degree of stereocontrol is
important.
To gain further insight into the observed reactivity differ-
ence between the exo and endo isomers, we next performed
transition-state calculations of the DARinv reaction of tetra-
zine with exo-norbornene 3 or endo-norbornene 4, respec-
tively, at the M06-2X/6-311+GACTHNUTRGNEUGN(d,p) level of theory. A func-
tional of the M06 family already showed good performance
for the computation of barrier heights in other similar in-
verse electron-demand Diels–Alder reactions.[19,36,37] The in-
fluence of water as solvent was further determined with the
polarizable continuum model (PCM).[38]
The addition of tetrazine to norbornene derivatives 3 and
4 can proceed from the exo- or from the endo-side, respec-
tively. As a result, four different products can be formed via
four different transition states. In all cases the calculated en-
ergetic barrier for the endo-addition is much higher than for
the exo-addition (see the Supporting Information). The cor-
responding reaction leading to the exo-addition proceeds for
exo-norbornene 3 with a lower barrier (DG° =15.18 kcal
molÀ1, Figure 2) than for endo-norbornene
4
(DG° =
15.83 kcalmolÀ1). These computations predict that the reac-
tion of tetrazine with 3 should be about three times faster
than the same reaction with 4.[39] This calculated increase in
the rate of the reaction is in excellent agreement with the
experimentally observed factor of 2.9 (see Table 1). The ex-
planation for the enhanced stabilization of the transition
Experimental Section
Kinetic measurements: An equal volume of a 0.1 mm solution of dipyri-
dyltetrazine in H2O/MeOH (9:1) and a solution of norbornene (1, 2.5, 5,
Chem. Eur. J. 2013, 00, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
3
&
ÞÞ
These are not the final page numbers!