Entropy versus tether strain effects on rates of intramolecular 1,3-dipolar cycloadditions of N-alkenylnitrones

Article abstract of DOI:10.1016/j.tetlet.2010.11.121

Intramolecular 1,3-dipolar cycloadditions of two N-alkenylnitrones are studied by means of density functional theory calculations. Cycloaddition of an acyclic 4-hexenylnitrone led to the expected isoxazolidine in 46% yield, but a 4-cycloheptenylnitrone did not react. Calculations of the transition states for cycloaddition indicate that although the cycloheptenyl nitrone has a more favorable activation entropy, the strain associated with distortion of the tethering groups into the required boat conformation disfavors the reaction of the cyclic substrate over the acyclic substrate by 8.7 kcal/mol.

Full text of DOI:10.1016/j.tetlet.2010.11.121

Tetrahedron Letters 52 (2011) 2181–2184
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Entropy versus tether strain effects on rates of intramolecular 1,3-dipolar
cycloadditions of N-alkenylnitrones
a,b,c,
⇑
, K. N. Houk c, , Andrew B. Holmes a,d, John Thompson e
⇑
Elizabeth H. Krenske
a
School of Chemistry, The University of Melbourne, Vic. 3010, Australia
b
c
Australian Research Council Centre of Excellence for Free Radical Chemistry and Biotechnology, Australia
Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095, USA
CSIRO, Materials Science and Engineering, Bayview Avenue, Clayton Vic. 3168, Australia
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
d
e
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 29 November 2010
Intramolecular 1,3-dipolar cycloadditions of two N-alkenylnitrones are studied by means of density func-
tional theory calculations. Cycloaddition of an acyclic 4-hexenylnitrone led to the expected isoxazolidine
in 46% yield, but a 4-cycloheptenylnitrone did not react. Calculations of the transition states for cycload-
dition indicate that although the cycloheptenyl nitrone has a more favorable activation entropy, the
strain associated with distortion of the tethering groups into the required boat conformation disfavors
the reaction of the cyclic substrate over the acyclic substrate by 8.7 kcal/mol.
Dedicated to Harry H. Wasserman on the
occasion of his 90th birthday
Keywords:
Nitrone
Ó 2010 Elsevier Ltd. All rights reserved.
1
,3-Dipolar cycloaddition
Density functional calculations
Transition states
Ring strain
Intramolecular 1,3-dipolar cycloadditions of nitrones with
alkenes have been employed in many natural product synthe-
To quantify the effect of the alkene configurations in 2 and 5,
transition states were first calculated for the cycloaddition of
1
–3
ses.
Scheme 1), we employed the intramolecular cycloaddition of the
-hexenyl nitrone 2, which furnished the isoxazolidine 3 in an
During the studies of the synthesis of carpamic acid (4)
(
4
NC(CH2)7
i
NC(CH2)7
4
overall yield of 46% based on oxime 1. In contrast, efforts to bring
about the intramolecular cycloaddition of the related cyclohepte-
nyl nitrone 5 failed to produce any of the expected cycloadduct
NOH
NHOH
1
ii
NC(CH2)7
iii
NC(CH2)7
6. A similar lack of reactivity was observed in an analogous system
N
O
N
O
when the alkene was contained in a 16- rather than a seven-mem-
bered ring. The reason for the difference in reactivity between acy-
clic 2 and cyclic 5 was not obvious, since the tethering of both
termini of the dipolarophile units in 5 might have been thought
to provide an additional entropic advantage. We have undertaken
a computational study to uncover the origin of this disparity.
Density functional theory calculations at the B3LYP/6-31G(d)
2
3
4
6% from 1
HO
steps
N
H
(CH ) COOH
2 7
4
carpamic acid
5
6
level were performed in GAUSSIAN 03. Previous theoretical studies
O
of the mechanisms and regioselectivities of nitrone 1,3-dipolar
cycloadditions have shown that these are usually concerted
processes.
N
O
O
N
iv
N
5
6
0
%
⇑
Corresponding authors. Tel.: +61 3 8344 0080; fax: +61 3 9347 8189 (E.H.K.);
tel.: +1 310 206 0515; fax: +1 310 206 1843 (K.N.H.).
E-mail addresses: ekrenske@unimelb.edu.au (E.H. Krenske), houk@chem.ucla.
edu (K.N. Houk).
Scheme 1. 1,3-Dipolar cycloaddition approaches to carpamic acid. Reagents and
conditions: (i) NaCNBH , HCl; (ii) MeCHO, Na SO ; (iii) toluene, reflux; 46% from 1;
(iv) benzene (40–80 °C) or toluene (110–115 °C) or t-amyl alcohol (115 °C).
3
2
4
0
040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.121

2
182
E. H. Krenske et al. / Tetrahedron Letters 52 (2011) 2181–2184
The activation enthalpy for TSC (23.5 kcal/mol) is only 2.1 kcal/
mol higher than that of the corresponding intermolecular cycload-
dition (TSA), and its free energy of activation (28.4 kcal/mol) is
6
.9 kcal/mol lower. Intramolecularity in this case produces an
entropic advantage. The entropies of activation are ꢀ46.7 e.u. for
TSA and ꢀ16.5 e.u. for TSC.
The activation enthalpy for TSD (33.5 kcal/mol) is 11.5 kcal/mol
higher than the intermolecular analog, TSB. The free energy of acti-
vation is 1.2 kcal/mol higher than the intermolecular value. Here,
à
the values of
D
S
are ꢀ46.5 e.u. for TSB and ꢀ12.0 e.u. for TSD.
à
The 8.7 kcal/mol difference in
DG between TSC and TSD is consis-
tent with the failure of 5 to undergo intramolecular cycloaddition
under the experimental conditions.
Similar results are obtained with use of the M06-2X
9
,10
Figure 1. Calculated transition structures for the cycloadditions of N-methyl-C-
methylnitrone with trans- and cis-2-butene. Bond distances in Å, activation energies
in kcal/mol at 298.15 K.
functional.
3
Single-point energy calculations at the M06-2X/6-
11+G(d,p) level on the B3LYP geometries gave activation enthal-
pies for TSC and TSD of 22.9 and 33.4 kcal/mol, respectively
z
11
(DH
). Details are provided in the Supplementary data.
OK
N-methyl-C-methylnitrone with trans- and cis-2-butene.7 The TS
To account for the difference in barriers, we computed the
energies associated with distorting various fragments of the sub-
strates 7 and 5 into the geometries observed in TSC and TSD. The
analysis is shown in Figure 3, where the transition structures are
reproduced on the left. In the center (C-1 and D-1), the atoms
connecting the nitrone to the alkene (2-butenyl fragment) have
been removed and replaced by H’s, to provide an estimate of
the distortion energies within the five-membered bond-forming
array alone. On the right (C-2 and D-2), the nitrone group has
geometries are shown in Figure 1. The configuration of the alkene
has little effect on either the geometry of the TS or the activation
energy. Both alkenes react via synchronous transition states, and
the activation barrier for the cis alkene (TSB) is 0.6 kcal/mol higher
than that for the trans alkene (TSA). This greater reactivity of trans
alkenes was previously noted by Huisgen.8
Transition structures for the intramolecular cycloadditions of 2
and 5 are shown in Figure 2. The acyclic N-alkenylnitrone 2 was
modeled by the methyl analog 7.
2
been replaced by NH and the remainder of the structure held
fixed, to provide an estimate of the energy associated with dis-
torting the tether to the geometry in the TS. The bond lengths,
angles, and dihedrals of the added H atoms were allowed to relax,
while all other structural features were held at the same values as
Both of the intramolecular TSs are less synchronous than the
intermolecular ones: the forming C–C bonds are shorter than the
forming C–O bonds, and this asynchronicity is more pronounced
in TSC than in TSD. In TSC, the forming six-membered ring adopts
a chair conformation. Other conformers were at least 2.9 kcal/mol
higher in energy. The two forming six-membered rings in TSD are
by contrast necessarily boats, and the cycloheptene ring is also
forced to adopt a boat conformation. Consequently, there are sig-
nificant eclipsing interactions along each C–C bond in the tethers.
1
2
in TSC or TSD.
Comparison of structures C-1 and D-1 indicates that the distor-
tions of the nitrone and alkene to their TS geometries are more dif-
à
ficult for TSD, but the difference is minor:
D
E
dist(nitrone) and
à
DEdist(alkene) are only 0.5 and 1.1 kcal/mol higher for TSD than
for TSC, respectively. A greater contribution to the difference in
barriers arises from the different orientation (dihedral angle) of
the nitrone with respect to the alkene in TSC and TSD. The less-
favorable overlap between the nitrone and the alkene in TSD leads
to a less stabilizing interaction between these two components:
z
DE
is 3.6 kcal/mol less favorable in TSD than in TSC. However,
int
the major factor that destabilizes TSD is the conformation of the
tether connecting the nitrone to the alkene. Distortion of cycloh-
eptenylamine to a geometry like that found in D-2 requires some
3
5.7 kcal/mol, whereas distortion of the hexenylamine to the
geometry found in C-2 requires only 27.9 kcal/mol. The difference
between these values, 8 kcal/mol, is a substantial part of the acti-
vation energy difference.
The distortion of the cycloheptene ring required to achieve the
TS is evident also in the conformational preferences of the reactant
nitrone. In Figure 4 are shown the lowest-energy chair and boat
conformers of 5. The chair conformation is preferred by 4.3 kcal/
mol. The distorted boat in TSD is even more difficult to access than
the boat reactant.
Intramolecular cycloaddition of a related N-alkenylnitrone con-
taining a cyclohexenyl group (8, Scheme 2) was reported by Oppol-
1
3
zer. The N-cyclohexenylmethylnitrone 8 furnished the cyclo-
adduct 9 in 64% yield. The transition structure for this transforma-
tion (TSE) and activation barriers are shown below. The newly-
forming six- and seven-membered rings in TSE both adopt chair-
à
like conformations, and the
D
G
value (27.2 kcal/mol) is 10 kcal/
mol lower than that for the intramolecular cycloaddition of 5.
In summary, we have elucidated the origins of the large
reactivity differences in intramolecular nitrone cycloadditions of
Figure 2. Two views of the calculated transition structures for the intramolecular
1
,3-dipolar cycloadditions of the acyclic N-alkenylnitrone 7 and the N-cycloalke-
nylnitrone 5.

E. H. Krenske et al. / Tetrahedron Letters 52 (2011) 2181–2184
2183
Figure 3. Calculated strain-related energies associated with various fragments of the intermolecular transition structures TSC and TSD. The structures C-1 and D-1 are the
structures obtained after removing the atoms connecting the nitrone to the butene component of the alkene (replacing unfilled valences with H). The structures C-2 and D-2
represent the geometry of the tether(s) at the TS, and were obtained by replacing the nitrone with an NH
2
group. The bond lengths, angles, and dihedrals of the added H atoms
were allowed to relax, but all other structural features were held at the same values as in TSC or TSD.
ering the barrier by 6.9 kcal/mol versus the acyclic analog. By
contrast, the cyclic reactant, 5, achieves an even larger entropic
advantage, but the reaction does not occur because of prohibitive
tether strain.
Acknowledgments
We thank the NSF (CHE-0548209 to K.N.H.), the Australian Re-
search Council (DP0985623 to E.H.K.), the EPSRC and Fisons Phar-
maceuticals plc (CASE studentship to J.T.), and CSIRO (Fellowship
to A.B.H.) for generous financial support, and the NCSA, UCLA
ATS (USA) and NCI NF (Australia) for computer resources. E.H.K.
thanks the ARC Centre of Excellence for Free Radical Chemistry
and Biotechnology for generous financial support.
Figure 4. Chair and boat conformations of cycloheptenyl nitrone 5.
Supplementary data
Supplementary data (the preparation and intramolecular dipo-
lar cycloaddition studies of 5, all B3LYP geometries and energies,
and M06-2X energies for selected species) associated with this
article can be found, in the online version, at doi:10.1016/
j.tetlet.2010.11.121.
Scheme 2. Oppolzer’s 1,3-dipolar cycloaddition of the cyclohexenylmethyl nitrone
8. Reagents and conditions: (i) toluene, reflux, 9 h, 64%.
References and notes
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little strain, it does provide a very large entropy advantage, low-

2
184
E. H. Krenske et al. / Tetrahedron Letters 52 (2011) 2181–2184
2
.
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4
5
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1
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11. Values of
à
D
H
at 0 K, calculated from the M06-2X single-point electronic
energies in conjunction with the B3LYP zero-point energies. The B3LYP/6-
à
31G(d) values of
DH at this temperature are 24.9 and 34.7 kcal/mol for TSC
and TSD, respectively. Use of M06-2X with the 6-31G(d) basis set provided
somewhat lower activation energies. Details are provided in the
Supplementary data.
6
.
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12. Replacement of the deleted atoms by Me groups rather than H atoms may have
provided a better model, but the constrained structures possessed imaginary
vibrational frequencies. The fully-optimized TSs corresponding to C-1 and D-1
are geometrically similar to TSA and TSB.
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1985, 41, 3497–3509.
5
1