Amino substituted bisketenes: Generation, structure, and reactivity

Article abstract of DOI:10.1021/jo062090h

Hitherto unknown diamino-substituted bisketenes with both free (14) and tethered (16) amino substituents have been generated by using laser flash photolysis for ring opening of the corresponding cyclobutenediones. The time-resolved kinetics of ring closur

Full text of DOI:10.1021/jo062090h

Amino Substituted Bisketenes: Generation, Structure,
and Reactivity
Nanyan Fu, Annette D. Allen, Shinjiro Kobayashi, Thomas T. Tidwell,* and Sinisa Vukovic
Department of Chemistry, UniVersity of Toronto, Toronto, Ontario M5S 3H6, Canada
Selvananthan Arumugam and Vladimir V. Popik
Department of Chemistry, UniVersity of Georgia, Athens, Georgia 30602-2556
Masaaki Mishima
Institute for Materials Chemistry and Engineering, 6-10-1 Hakozaki, Fukuoka, 812-8581 Japan
ttidwell@chem.utoronto.ca
ReceiVed October 9, 2006
Hitherto unknown diamino-substituted bisketenes with both free (14) and tethered (16) amino substituents
have been generated by using laser flash photolysis for ring opening of the corresponding cyclobutene-
diones. The time-resolved kinetics of ring closure of the amino bisketenes back to the cyclobutenediones
were measured by IR or UV spectroscopy, and give first-order rate constants which vary by a factor of
7.5 × 104, and the bis(Me2N) bisketene 14 is the most reactive in ring closure that has been reported.
Rate constants for ring closure of these and previously observed bisketenes vary by a factor of 1013. The
dialkylamino bisketenes 16 (R ) Me, n-Bu) with tethered substituents and restricted geometries are less
reactive than the bis(Me2N) bisketene 14 by factors of 1700 and 540, respectively. Computational results
obtained with DFT methods suggest angle strain in the tethered cyclobutenediones 15 inhibits facile
cyclization of bisketenes 16.
Introduction
Aminoketenes have been calculated to be destabilized,2 and
the stability of the amino-substituted ketenes 1 and 2 is
attributable to steric protection by the bulky substituents.
Computations indicate that the parent aminoketene (3) is most
stable with pyramidalized nitrogen so that the lone pair is in
the ketene plane as is found in 1b, and the syn- and anti-
periplanar geometries 3a,b are close in energy.1,2 The coplanar
structure 3c with the lone pair parallel to the ketene π system
is calculated to be less stable and not an energy minimum,1,2
but the rigid planar ring forces this geometry for 2.1
The first report of both the direct observation and the isolation
of amino-substituted ketenes has recently appeared,1a although
these species have been sought since the early days of ketene
chemistry.1b The acyclic ketenes 1 and the cyclic derivative 2
were prepared by the room temperature reaction of the corre-
sponding stable carbenes with carbon monoxide, and the
structures were confirmed by spectroscopic evidence, and for
the crystalline products 1b and 2 by X-ray crystallography
(Scheme 1).1 Reactivity studies of these species have not been
reported, but their isolation at room temperature is highly
unusual for ketenes with amino, oxygen, or halo substituents.
The favored nitrogen pyramidalization and coplanar alignment
of the orbital containing the nitrogen lone electron pair in
(2) (a) Gong, L.; McAllister, M. A.; Tidwell, T. T. J. Am. Chem. Soc.
1991, 113, 6021-6028. (b) McAllister, M. A.; Tidwell, T. T. J. Org. Chem.
1994, 59, 4506-4515. (c) Gupta, V. P., Sharma, A.; Agrawal, S. G. Bull.
Korean Chem. Soc. 2006, 27, 1297-1304. (d) Badawi, H. M. J. Mol. Struct.
2005, 726, 253-260.
(1) (a) Lavallo, V.; Canac, Y.; Donnadieu, B.; Schoeller, W. W.; Bertrand,
G. Angew. Chem., Int. Ed. 2006, 45, 3488-3491. (b) For a commentary
see: Tidwell, T. T. Angew. Chem., Int. Ed. 2006, 45, 5580-5582.
10.1021/jo062090h CCC: $37.00 © 2007 American Chemical Society
Published on Web 01/23/2007
J. Org. Chem. 2007, 72, 1951-1956
1951

Fu et al.
SCHEME 1. Generation of Stable Aminoketenes
SCHEME 2. Amidoketene Generation
SCHEME 3. Mu1nchnone-Amidoketene Interconversion
and Capture
aminoketenes contrasts with the favored parallel arrangement
of the electron pair containing the p orbital of nitrogen to the
adjacent carbonyl group π bond in amides.3 The strong
preference for the conjugated geometry in amides is highlighted
by the recent first preparation of a well-characterized tetrafluo-
roborate salt 4b of the parent 2-quinuclidone structure 4a.3a The
parent amide 4a lacking normal amide conjugation has so far
not been observed from 4b, which reacts with t1/2 < 15 s with
water forming ring opened 5 or a salt as the only observed
product.3a Smaller deviations from planarity of the amide
nitrogen in 7-azabicyclo[2.2.1]heptane amides have been at-
tributed to CNC angle strain and allylic strain.3d
accepted that highly reactive ketenes are usually formed under
these conditions, but are often too short-lived for direct
observation.4d,6d,e Many further examples of nitrogen-substituted
ketenes, including aminoketenes, have been generated by
analogous procedures, especially for use in â-lactam formation.6b-d
Winter and Pracejus prepared substituted phthalimidoketenes
9 by dehydrochlorination of the corresponding acyl chlorides
with tertiary amines, and evidence for ketene formation for
R ) Bn, Ph, and i-Pr in solution was provided by the observation
of characteristic ketene bands at 2141, 2136, and 2125 cm-1
respectively,7a while the ketene with R ) t-Bu was obtained as
a solid: mp 96-98 °C, IR 2134 cm-1 7a
Steric protection from
,
.
the two bulky groups and delocalization of the amido nitrogen
lone pair evidently permit this to be stable even in the solid
state.
Mu¨nchnone 10a was proposed to exist in equilibrium with a
low concentration of the amidoketene 10b, which was not
observed directly but underwent [2+2] cycloaddition with
imines forming â-lactams 10c (Scheme 3).7b Further examples
of such Mu¨nchnone-amidoketene equilibria have recently been
reported.7c,d
Cyclobutenediones 11 have been extensively utilized for the
generation of 1,2-bisketenes 12. When the bisketenes possess
ketene-stabilizing silyl substituents they are of comparable or
greater stability compared to 11, and the transformations may
be carried out thermally.4d,8c,d With less electropositive substit-
uents the bisketenes 12 are less stable than the cyclobutenediones
11, but may be generated by photolysis, and their conversion
After early speculation about nitrogen-substituted ketenes4
these ultimately proved to be of significant utility in the race to
prepare penicillins, and evidently the first reported successful
preparation of a nitrogen-substituted ketene was reported by
Sheehan and co-workers.5 The reaction of succinimidoacetyl
chloride 6a with triethylamine generated ketene 6b as an
unobserved intermediate that was captured in situ by ketene-
imine [2+2] cycloaddition with the thiazoline 7 forming 8a
(Scheme 2), which was used in the synthesis of the 5-phenyl
penicillin 8b.5,6 Phthalimidoketene 9 (R ) H) was generated
and trapped in a similar fashion.6
Amido-substituted ketenes were considered as possible
(5) (a) Sheehan, J. C.; Buhle, E. L.; Corey, E. J.; Laubach, G. D.; Ryan,
J. J. J. Am. Chem. Soc. 1950, 72, 3828-3829. (b) Sheehan, J. C.; Laubach,
G. D. J. Am. Chem. Soc. 1951, 73, 4376-4780.
intermediates in these reactions,6a,b and it is now generally
(3) (a) Tani, K.; Stoltz, B. M. Nature 2006, 441, 731-734. (b) For a
commentary see: Wasserman, H. H. Nature 2006, 441, 699-700. Also
see ref 3c. (c) Clayden, J.; Moran, W. J. Angew. Chem., Int. Ed. 2006, 45,
7118-7120. (d) Otani, Y.; Nagae, O.; Naruse, Y.; Inagaki, S.; Ohno, M.;
Yamaguchi, K.; Yamamoto, G.; Uchiyama, M.; Ohwada, T. J. Am. Chem.
Soc. 2003, 125, 15191-15199.
(4) (a) Staudinger, H.; Kupfer, O. Ber. Dtsch. Chem. Ges. 1911, 44,
1638-1640. (b) Staudinger, H.; Anthes, E.; Schneider, H. Ber. Dtsch. Chem.
Ges. 1913, 46, 3539-3531. (c) For a review of recent developments in
ketene chemistry see: Tidwell, T. T. Eur. J. Org. Chem. 2006, 563-576.
(d) Tidwell, T. T. Ketenes, 2nd ed.; Wiley: Hoboken, NJ, 2006.
(6) (a) Sheehan, J. C.; Ryan, J. J. J. Am. Chem Soc. 1951, 73, 1204-
1206. (b) Sheehan, J. C.; Ryan, J. J. J. Am. Chem Soc. 1951, 73, 4367-
4372. (c) Sheehan, J. C.; Corey, E. J. Org. React. 1957, 9, 388-408. (d)
Palomo, C.; Aizpurua, J. M. Science of Synthesis (Houben-Weyl); Bellus,
D., Danheiser, R., Eds.; Thieme Verlag: Stuttgart, Germany, 2006; Vol.
23.6. (e) Reichen, W. Chem. ReV. 1978, 78, 569-588.
(7) (a) Winter, S.; Pracejus, H. Chem. Ber. 1966, 99, 151-159. (b)
Huisgen, R.; Funke, E.; Schaefer, F. C.; Knorr, R. Angew. Chem., Int. Ed.
1967, 6, 367-368. (c) Dhawan, R.; Dghaym, R. D.; Arndtsen, B. A.
J. Am. Chem. Soc. 2003, 125, 1474-1475. (d) Dhawan, R.; Dghaym,
R. D.; St. Cyr, D. J.; Arndtsen, B. A. Org. Lett. 2006, 8, 3927-3930.
1952 J. Org. Chem., Vol. 72, No. 6, 2007

Amino-Substituted Bisketenes
TABLE 1. Rate Constants for Ring Closure of Bisketenes 14 and
16 at 25 °C
SCHEME 4. Cyclobutenedione-Bisketene Interconversion
substituents
method, solvent
k (s-1
)
Me2N (14a)
MeNH (14b)
NH2 (14c)
PhNH (14d)
16 (R ) Me)
UV,a CH3CN
UV,b CH3CN
UV,c CH3CN
UV,a CH3CN
UV,d CH3CN
UV,e CDCl3
UV,e isooctane
UV,f CH3CN
IR,g CH3CN
(9.58 ( 0.38) × 107
(1.84 ( 0.32) × 105
(1.28 ( 0.13) × 103
(6.72 ( 0.25) × 106
(5.54 ( 0.27) × 104
(1.58 ( 0.08) × 104
(5.86 ( 0.34) × 103
(1.64 ( 0.06) × 105
(1.82 ( 0.08) × 105
1.77 × 105 (average)h
(4.02 ( 0.20) × 104
(1.04 ( 0.02) × 104
SCHEME 5. Preparation of Amino-Substituted
Cyclobutenediones 13 and 15, and Conversion to Bisketenes
14 and 16
16 (R ) n-Bu)
UV,e CDCl3
UV,e isooctane
a Monitoring wavelength 330 nm. b Monitoring wavelength 289 nm.
c Monitoring wavelength 280 nm. d Monitoring wavelength 300 and 283
nm. e Monitoring wavelength 315 and 275 nm. f Monitoring wavelength 290
nm. g Monitoring wavelength 2064, 2116 cm-1
.
h Average of the IR and
UV rate constants.
back to 11 may be observed spectroscopically, including
derivatives with ketene destabilizing chlorine and oxygen
substituents (Scheme 4).4d,8 Aminocyclobutenediones have been
extensively studied,9 and are biologically active,9g with applica-
tions in materials chemistry,9c but have not previously been
examined as bisketene precursors.
Results
Diamino-substituted cyclobutenediones9 with both free (13a,
R1R2N ) Me2N; 13b, R1R2N ) MeNH; 13c, R1R2N ) NH2;
13d, R1R2N ) PhNH) and tethered (15, R ) Me, n-Bu)
substituents were prepared from substitution reactions of amines
or 1,2-diamines, respectively, with diethoxycyclobutenedione
(Scheme 5). The X-ray structure of the tethered cyclobutene-
dione 15 (R ) Me) was determined, as shown in Figure S5
(Supporting Information), and conversions to the bisketenes 14
and 16 were carried out by using laser flash photolysis
(Scheme 4).
Upon laser flash photolysis of 13 and 15 in CH3CN and other
solvents with previous techniques8e,10a,b the respective bisketenes
14 and 16 were generated as transient species, and the kinetics
of reformation of the cyclobutenediones were measured by the
increase in the UV absorption at wavelengths given with the
observed rate constants in Table 1. A representative kinetic trace,
for the reformation of the UV absorbance for 13a in CH3CN,
is shown in Figure 1. The variation of the rate constants with
solvent polarity CH3CN > CDCl3 > isooctane is similar to that
FIGURE 1. Recovery of UV absorption of cyclobutenedione 13
(R1R2N ) Me2N) from the bisketene 14 formed by laser flash
photolysis.
observed for other bisketenes, which was attributed to greater
polarity of the incipient product cyclobutenediones.8d
The identification of the bisketene 16 (R ) n-Bu) was
confirmed by observation of distinctive ketenyl IR bands at 2064
and 2116 cm-1 in CH3CN (Figure 2), and the kinetics of the
decay of this absorption were measured by IR, and gave a rate
constant in good agreement with the value measured by UV
for reformation of the cyclobutenedione 15 (Table 1).
Selected reactions were also examined computationally with
use of DFT methods at the B3LYP/6-31G(d) level, using
(9) (a) Frontera, A.; Morey, J.; Oliver, A.; Pin˜a, M. N.; Quin˜onero, D.;
Costa, A.; Ballaster, P.; Deya, P. M.; Anslyn, E. V. J. Org. Chem. 2006,
71, 7185-7195. (b) Muthyala, R. S.; Subramanian, G.; Todaro, L. Org.
Lett. 2004, 6, 4663-4665. (c) Lunelli, B.; Roversi, P.; Ortoleva, E.; Destro,
R. J. Chem. Soc., Faraday Trans. 1996, 92, 3611-3623. (d) Griffiths,
G. R.; Rowe, M. D.; Webb, G. A. J. Mol. Struct. 1971, 8, 363-371. (e)
Maahs, G.; Hegenberg, P. Angew. Chem., Int. Ed. 1966, 5, 888-893. (f)
Thorpe, J. E. J. Chem. Soc. B 1968, 435-436. (g) Verniest, G.; Colpaert,
J.; To¨rnoos, K. W.; De, Kimpe, N. J. Org. Chem. 2005, 70, 4549-4552.
(h) Ehrhardt, H.; Hu¨nig, S.; Pu¨tter, H. Chem. Ber. 1977, 110, 2506-2523.
(10) (a) Allen, A. D.; Fedorov, A. V.; Najafian, K.; Tidwell, T. T.;
Vukovic, S. J. Am. Chem. Soc. 2004, 126, 15777-15783. (b) Acton,
A. W.; Allen, A. D.; Antunes, L. M.; Fedorov, A. V.; Najafian, K.; Tidwell,
T. T.; Wagner, B. D. J. Am. Chem. Soc. 2002, 124, 13790-13794.
(c) Gaussian 98, Revision A-9; Gaussian, Inc.: Pittsburgh, PA, 1998.
(8) (a) Allen, A, D.; McAllister, M. A.; Tidwell, T. T.; Zhao, D. Acc.
Chem. Res. 1995, 115, 265-271. (b) Allen, A. D.; Lough, A. J.; Tidwell,
T. T. Chem. Commun. 1996, 2171-2172. (c) Allen, A. D.; Colomvakos,
J. D.; Egle, I.; Lusztyk, J.; McAllister, M. A.; Tidwell, T. T.; Wagner,
B. D.; Zhao, D.-c. J. Am. Chem. Soc. 1995, 117, 7552-7553. (d) Allen,
A. D.; Colomvakos, J. D.; Diederich, F.; Egle, I.; Lusztyk, J.; McAllister,
M. A.; Rubin, Y.; Tidwell, T. T.; Wagner, B. D.; Zhao, D.-c. J. Am. Chem.
Soc. 1997, 119, 12045-12050. (e) Aguilar-Aguilar, A.; Allen, A. D.; Pen˜a-
Cabrera, E.; Fedorov, A.; Fu, N.; Henry-Riyad, H.; Kobayashi, S.;
Leuninger, J.; Schmid, U.; Tidwell, T. T.; Verma, R. J. Org. Chem. 2005,
71, 9556-9561. (f) McAllister, M. A.; Tidwell, T. T. J. Am. Chem. Soc.
1994, 116, 7233-7238.
J. Org. Chem, Vol. 72, No. 6, 2007 1953

Fu et al.
be affected by a separate resonance effect of the substituents
on the ketenyl moieties and the incipient product cyclobutene-
diones in the transition states. Particularly for π-electron donor
substituents such as OH and NH2, these might be expected to
enhance bisketene ring closure due to their strong π-electron
+
donor character. This latter effect would be related to σp
parameters. Therefore for the larger set of 25 substrates with
substituent parameters now available both one and two param-
eter correlations were tested, as shown in eqs 2 and 3,
respectively. However, it may be seen that the correlation
coefficients are essentially the same, and furthermore that the
error in the dependence upon the σp+ parameters is quite large.
Thus specific inclusion of the latter effect does not improve
the correlation, and the reactivity is best correlated by the SE
parameters alone (Figure 3). While this was unexpected it
appears that the effect of the π-electron donating ability of the
substituents is already included in the SE parameters. The
relevant SE and σp+ parameters used are compiled in Table S6
(Supporting Information).
FIGURE 2. Decay of IR absorption (2-µs intervals between curves)
of bisketene 16 (R ) n-Bu) forming cyclobutenedione 15.
Gaussian 98.10c These methods have proven to be reliable in
other recent studies of ketene reactions.10a,b For comparison,
cyclobutenediones 11, R ) H and Me, were also studied. The
energies of cyclobutenediones 13 and 15, the corresponding
bisketenes 14 and 16, and the transition states 17 and 18 for
The reactivities of the amino-substituted cyclobutenediones
14 (R1R2N ) Me2N, PhNH, MeNH, and NH2) are not well
accounted for by this correlation, as the reactivities differ by a
factor of 7.5 × 104, but computations (Table S7, Supporting
Information) indicate these substituents have very similar SE
values. Calculated barriers for ring closure (Table 2) do,
however, predict the relative reactivities in ring closure for 14
(R1R2N ) Me2N, MeNH, and NH2), as discussed below.
The structure of the cyclobutenedione 13 (R1R2N ) PhNH)
has been proposed to have a syn arrangement of the phenyls
relative to carbonyl groups.9b This structure would be favored
for steric reasons, and our computation indicates 13 (R1R2N )
MeNH) has a similar structure in the most stable conformation,
although a planar structure with the Me group anti to the
carbonyl oxygen is also a minimum energy structure. Our
computed structure for 13 (R1R2N ) Me2N) (Figure S5,
Supporting Information) indicates an essentially coplanar struc-
ture, with dihedral angles of 174.2° for C1C2C3N and -8.4°
for NC2C3N (numbering as in 21). No evidence has been found
in reported structures of bis(diamino) cyclobutenediones 13 or
15 obtained by computation or X-ray of intramolecular hydrogen
bonding interactions involving the amino groups.
their interconversion were obtained, and the energy changes are
summarized in Table 2. Details of the energies and geometries
are given in Tables S3-S5 (Supporting Information). The results
for 11 and 12 (R ) H) are in reasonable agreement with
previously obtained ab initio results at the MP2/6-31G* level:
Erel(TS) ) 30.8 kcal/mol, Erel(12) ) 3.2 kcal/mol, ∆E*(ring
closure) ) 27.6 kcal/mol.8f
Discussion
The measured rate constants for ring closure of the bisketenes
14 are large in all cases, with relative rate constants of 7.5 ×
104, 5.2 × 103, 140, and 1.0 for R1R2N ) Me2N, PhNH, MeNH,
and NH2, respectively. The rate constant for ring closure for
14a (R1R2N ) Me2N) is the greatest that has been measured
for any 1,2-bisketene, of 30 examples, and even exceeds by a
factor of 5000 that for 20 forming 19 (Scheme 6), in which
there is a gain in aromatic stabilization for forming the
substituted benzene ring. The rate constant for 14a (R1R2N )
Me2N) is greater than that of 12 (substituents Me3Si and Me),
the least reactive bisketene for which we have measured a rate
constant, by a factor of 2 × 1013, and exceeds that estimated
for 12 (R ) Me3Si) by a factor of 1018.8d These results
demonstrate the powerful ketene destabilizing effect and cy-
clobutenedione stabilization by amino groups.
The effect of substituents on ketene stability has been
previously examined by using computed isodesmic energy
parameters (SE) (in kcal/mol) for substituents on ketenes,
calculated from eq 1.8d These gave a fair correlation of rate
constants for ring closure of 19 bisketenes in isooctane or CH3-
CN. However, it was also considered that the reactivities might
The variation in the relative rates for ring closure of 14
(R1R2N ) Me2N, PhNH, MeNH, and NH2) of 7.5 × 104:5.2 ×
103:140:1 is striking. The electron donor effect of the groups
in stabilizing the incipient cyclobutenediones as measured by
1954 J. Org. Chem., Vol. 72, No. 6, 2007

Amino-Substituted Bisketenes
TABLE 2. B3LYP/6-31G(d) Calculated Relative Energies (kcal/mol)a for Interconversion of Cyclobutenediones 11, 13, or 15 with Bisketenes
12, 14 or 16, Respectively, and Rate Constants for Ring Closure
k (s-1) 25 °C
cyclobutenedione
Erel(11, 13, or 15)
Erel(TS)
Erel(12, 14, or 16)
∆E*(ring closure)
CH3CN
11 (R ) H)
0.00
0.00
0.00
0.00
0.00
0.00
0.00
28.42
33.32
38.84
42.83
42.54
45.92
50.31
1.74
14.55
35.54
36.85
35.25
32.67
37.99
26.68
18.77
3.30
5.98
7.29
b
11 (R ) Me)
3.60 × 10-2 c
9.58 × 107
1.84 × 105
1.28 × 103
b
13 (R1R2N ) Me2N)
13 (R1R2N ) MeNH)
13 (R1R2N ) NH2)
15 (R ) H)
15 (R ) Me)
a With ZPVE. b Not determined. c Reference 8d.
13.25
12.32
5.54 × 104
SCHEME 6. Interconversion of Benzocyclobutenone 19 and
Bisketene 20
the respective σp constants11 of -1.70, -1.40, -1.81, and
+
-1.30, respectively, would contribute to this difference, although
+
the data for R ) MeNH do not fit the trend. However, the σp
constant for this substituent11c was obtained in a separate study
by a different laboratory than the others, and this may cause
the inconsistency. The calculated barriers for ring closure of
14 (R1R2N ) Me2N, MeNH, and NH2) of 3.30, 5.98, and 7.29
kcal/mol, respectively, fit very well with the experimental
results.
The X-ray structure of the tethered cyclobutenedione 15
(R ) Me) (Figure S5, Supporting Information) clearly shows
the near planar geometry at the amino substituents with sp2
hybridization at nitrogen to permit conjugative electron donation
to the cyclobutenedione ring. In the calculated structure of the
derived bisketene the nitrogen has, however, assumed a pyra-
midalized geometry (sum of the C-N-C bond angles 338.7°),
which reduces the destabilizing conjugative interaction of the
amino substituents and the ketenyl groups. Sums of calculated
bond angles at nitrogen for bisketenes 14 are 341.5° (R1R2N )
Me2N), 336.6° (R1R2N ) MeNH), and 330.4° (R1R2N ) NH2),
showing increasing planarization of the nitrogen with increasing
substitution. This trend is consistent with a steric effect as the
nitrogen becomes more heavily substituted.12
The tethered diamino-substituted bisketenes 16 (R ) Me and
n-Bu) have similar rate constants for ring closure, and these
are the same as or smaller than those of the free bisketenes 14
(R1R2N ) Me2N, PhNH, and MeNH), but larger than that for
14 (R1R2N ) NH2). As the tethered bisketenes 16 may appear
constrained to conformations closer to the coplanar geometries
of the cyclobutenediones, it might have been expected that these
would have enhanced reactivity in ring closure compared to
acyclic analogues. The calculated barrier (Table 2) for ring
FIGURE 3. Correlation of rate constants for bisketene ring closure
with ketene stabilization parameters SE.
closure of the tethered bisketene 16 (R ) Me) of 12.32 kcal/
mol is greater than those of 14 (R1R2N ) Me2N, MeNH, and
NH2), and as noted above the experimental results follow the
calculated barriers, except for 14 (R1R2N ) NH2).
Examination of the calculated bond distances of the reactants,
transition states, and products as defined in Table S4 and
structure 21 reveals that the cyclobutenediones 11 with R ) H
or Me have cyclobutene-like structures, with C2C3 bond lengths
of 1.355 and 1.368 Å, while C1C2 and C1C4 range from 1.508
to 1.587 Å. However, for amino-substituted cyclobutenediones
13 (R1R2N ) Me2N, MeNH, or NH2) and for the tethered
analogues 15 (R ) H, CH3) there is a trend toward equalization
of the bond distances, with longer C2C3 bonds and shorter C1C2
and C3C4 bonds, consistent with conjugative electron donation
from nitrogen to the ring. In the transition states for ring closure
the length of the forming C1C4 bond is greater for the amino-
substituted derivates than for 11 (R ) H, CH3), consistent with
the lower barriers and earlier transition states for ring closure
of the amino bisketenes. The dihedral bond angles C1C2C3C4
between the forming ketenyl groups in the transition states are
21.6° and 26.9° for the cyclobutenedione precursors 11 (R )
H and Me, respectively) and 29.7° (Me2N), 29.8° (MeNH), and
29.8° (NH2) for the corresponding amino-substituted derivatives,
also consistent with the earlier transition states and lower barriers
for ring closure of the latter group. For the tethered derivative
from 15 (R ) Me), this angle is 26.0°, suggesting a greater
barrier for ring closure than for the other amines, consistent
with experiment. For the bisketenes the C1C2C3C4 dihedral
angles (Table S4) range from 78.3° to 74.4° for 12 (R ) H,
(11) (a) Brown, H. C.; Okamoto, Y. J. Am. Chem. Soc. 1958, 80, 4979-
4987. (b) Hansch, C.; Leo, A.; Taft, R. W. Chem. ReV. 1991, 91, 165-
195. (c) Epstein, L. M.; Ashkinadze, L. D.; Shubina, E. S.; Kravtsov,
D. N.; Kazitsyna, L. A. J. Organomet. Chem. 1982, 228, 53-59.
(12) In ref 3d the sum of the bond angles at nitrogen in amides, designated
as θ, and the hinge angle R (the angle between the bond to the carbonyl
group in amides and the plane defined by the nitrogen atom and the two
other substituents) are designated as measures of the planarity of the nitrogen
atom. The angle R has values of 138.18, 130.25, and 128.08 for 14 (R1R2N
) Me2N, MeNH, and NH2, respectively), consistent with the trend in the
sum of the bond angles.
J. Org. Chem, Vol. 72, No. 6, 2007 1955

Fu et al.
Me) and 14 (R1R2N ) NH2, and MeNH), but are 69.6° for 14
(R1R2N ) Me2N) and 67.1° and 76.3° for 16 (R ) H and Me),
respectively.
under reduced pressure. The residue was purified by flash chro-
matography (silica gel, EtOAc/hexanes 2:1 v/v to EtOAc) to afford
15 (R ) n-Bu) (162 mg, 56%) as white crystals, mp 185.5-186.5
1
°C. H NMR (400 MHz, CDCl3) δ 3.51 (t, 4H, J ) 6.8 Hz), 3.42
The cause of the (1.7 × 103)-fold lesser reactivity in ring
closure of the tethered bisketene 16 (R ) Me) compared to 14
(R1R2N ) Me2N) does not appear to be due to electronic effects,
as the nitrogen in both cases is calculated to be planarized and
coplanar with the cyclobutenedione, and pyramidalized in the
bisketenes. However, in the dialkylamino cyclobutenedione 13
(R1R2N ) Me2N) the calculated bond angle Me2N-CdC is
139.0°, while for the tethered dialkylamino cyclobutenedione
15 (R ) Me) the corresponding angle N-CdC is constrained
to an angle of 124.2°. This angle strain in the tethered
cyclobutenedione is a plausible candidate for the cause of the
lower reactivity in ring closure of the corresponding bisketene.
In summary 1,2-bis(amino)-substituted 1,2-bisketenes with
both free and tethered substituents have been generated, and
their ring closure to the corresponding cyclobutenediones has
been observed by spectroscopic methods for the first time. The
bisketene 14 (R1R2N ) Me2N) is the most reactive bisketene
in ring closure to the corresponding cyclobutenedione that has
been measured, in stark contrast to the stability of the highly
crowded stable aminoketenes 1 and 2,1 and there is an enormous
range in reactivities of more than 1013 in measured rate constants
for ring closure of 1,2-bisketenes. A semiquantitative correlation
of the reactivities is found based on substituent parameters SE,
and calculations of barriers for ring closure with DFT methods
are largely consistent with the results. Ring strain in the tethered
cyclobutenediones 15 appears to inhibit their reformation by
ring closure.
(s, 4H), 1.63-1.71 (m, 4H), 1.30-1.41 (m, 4H), 0.95 (t, 6H, J )
7.6 Hz).13C NMR (100 MHz, CDCl3) δ 180.5, 167.6, 51.0, 45.5,
30.3, 19.9, 13.9. EIMS (m/z) 250 (M+), 179, 151, 137, 111, 96.
HREIMS (m/z) calcd for C14H22N2O2 250.1681, found 250.1685.
IR (KBr) 1593 cm-1. UV/vis (isooctane) λmax (ꢀ) 278 nm (3.65 ×
104), 300 nm (4.00 × 104).
Kinetic Measurements. Kinetic measurements by UV spec-
troscopy of the reformation of cyclobutenones 13 and 15 from
bisketenes 14 (R1R2N ) MeNH, NH2, PhNH) and 16 (R ) Me
and n-Bu), respectively, were measured at the University of Toronto
with apparatus described previously.10a,b Cyclobutenedione pho-
tolysis with an excimer laser (XeCl, 308 nm) was used to generate
the transient bisketenes, except for 13 (R1R2N ) MeNH), for which
a Nd:YAG laser (266 nm) was employed, with observation of the
reformation of the cyclobutenedione absorption. Substrate concen-
trations of 5 × 10-6 M (13, R1R2N ) NH2), 5.7 × 10-5 (13, R1R2N
) MeNH), 4.0 × 10-5 (13, R1R2N ) PhNH), (1.5 to 5.8) × 10-6
(15, R ) Me), and 3.5 × 10-6 to 2 × 10-5 M (15, R ) n-Bu) were
used, with either 1 or 5 cm cells. Kinetic measurements by UV
spectroscopy on 14 (R1R2N ) Me2N) were carried out at the
University of Georgia, LFP experiments were conducted with ca.
5 × 10-5 M solutions of the substrate in HPLC-grade acetonitrile
(5 µL of 0.02 M stock solution in DMSO was injected into 2 mL
of acetonitrile). For excitation the 355 nm frequency tripled output
of a Nd:YAG laser was employed. Reformation of absorption of
13 (R1R2N ) Me2N) was observed at 330 nm.
Kinetic measurements on 16 (R ) n-Bu) by IR were carried out
in Japan with ketene generation with a Nd:YAG laser (266 nm)
and 1.0 × 10-3 M solutions with observations at 2064 and
2116 cm-1
.
Experimental Section
Acknowledgment. Financial support by the Natural Sciences
and Engineering Research Council of Canada and the Petroleum
Research Fund, administered by the American Chemical Society,
is gratefully acknowledged. Computations were carried out with
the High-Performance Computer Cluster at the University of
Toronto at Scarborough.
The cyclobutenediones 13a (R1R2N ) Me2N),9b 13b (R1R2N )
MeNH),9h 13c (R1R2N ) NH2),9d 13d (R1R2N ) PhNH),9b,d and
15 (R ) Me)9h are known compounds prepared by literature
procedures.
2,5-Di-n-butyl-2,5-diazabicyclo[4.2.0]oct-1(6)-ene-7,8-dione (15,
R ) n-Bu). To a stirred solution of diethyl squarate (196 mg, 1.15
mmol) in dry Et2O (10 mL) was added a solution of N,N′-di-n-
butylethylenediamine (199 mg, 1.15 mmol) in dry Et2O (5 mL).
The mixture was stirred at room temperature overnight and then
concentrated under reduced pressure. To the residue was added THF
(75 mL) and the solution was refluxed overnight and concentrated
Supporting Information Available: Experimental and com-
putational details. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO062090H
1956 J. Org. Chem., Vol. 72, No. 6, 2007