Nucleophile-induced intramolecular dipole 1,5-transfer and 1,6-cyclization: Experimental and ab initio studies of formation, thermolysis, and molecular and electronic structures of 3,6-diphenyl-1-propanesulfenimido-1,2,4,5-tetrazine

Article abstract of DOI:10.1021/ja993884z

Reaction of dichlorobenzaldazine (2) with sodium azide followed by 1-propanethiol/Et₃N furnished tetrazine ylide 1 as the main product. The structure of this unprecedented ylide was confirmed with single-crystal X-ray analysis [C₁₇H₁₇N₅S, monoclinic P2₁/n a = 6.8294(4) A, b = 13.6781(9) A, c = 17.5898(12) A, β = 90.666(1)°, Z = 4] and favorably compared with the results of ab initio calculations. The mechanisms of formation of the ylide and its thermal decomposition to 2,5-diphenyltetrazine (5) were investigated using ab initio methods and correlated with the experimental observations. The results suggest that formation of 1 involves intramolecular cyclization of a nitrile imine and thermolysis of 1 might generate a sulfenylnitrene. The formation of 1 is considered to be the first example of a potentially more general reaction.

Full text of DOI:10.1021/ja993884z

J. Am. Chem. Soc. 2000, 122, 2087-2095
2087
Nucleophile-Induced Intramolecular Dipole 1,5-Transfer and
1,6-Cyclization: Experimental and ab Initio Studies of Formation,
Thermolysis, and Molecular and Electronic Structures of
3,6-Diphenyl-1-propanesulfenimido-1,2,4,5-tetrazine
Piotr Kaszynski*,† and Victor G. Young, Jr.‡
Contribution from the Organic Materials Research Group, Department of Chemistry,
Vanderbilt UniVersity, NashVille, Tennessee 37235, and X-ray Crystallographic Laboratory,
Department of Chemistry, UniVersity of Minnesota, Twin Cities, Minnesota 55455
ReceiVed NoVember 1, 1999
Abstract: Reaction of dichlorobenzaldazine (2) with sodium azide followed by 1-propanethiol/Et3N furnished
tetrazine ylide 1 as the main product. The structure of this unprecedented ylide was confirmed with single-
crystal X-ray analysis [C17H17N5S, monoclinic P21/n a ) 6.8294(4) Å, b ) 13.6781(9) Å, c ) 17.5898(12) Å,
â ) 90.666(1)°, Z ) 4] and favorably compared with the results of ab initio calculations. The mechanisms of
formation of the ylide and its thermal decomposition to 2,5-diphenyltetrazine (5) were investigated using ab
initio methods and correlated with the experimental observations. The results suggest that formation of 1
involves intramolecular cyclization of a nitrile imine and thermolysis of 1 might generate a sulfenylnitrene.
The formation of 1 is considered to be the first example of a potentially more general reaction.
Introduction
Results and Discussion
Intramolecular reactions of 1,3-dipoles provide one of the
most versatile ways to construct heterocyclic rings.1 Among
these reactions is the cyclization of conjugated dipoles, which
typically yields five-membered, and rarely seven-membered
rings.2,3 To our knowledge, the formation of six-membered rings
by cyclization of conjugated 1,3-dipoles has never been
observed, and even if the structure permits 1,6-cyclization,
formation of a five-membered ring dominates.4 Recently, we
discovered that certain conjugated 1,3-dipoles readily close to
six-membered rings.
Synthesis of 1. 3,6-Diphenyl-1-propanesulfenimido-1,2,4,5-
tetrazine (1) was obtained in a one-pot reaction. Dichloride 2
was reacted with 1 equiv of sodium azide under phase transfer
catalysis conditions at room temperature followed by 1 equiv
of 1-propanethiol and triethylamine. The major product, tetrazine
1, was isolated in about 40-50% yield by chromatography as
the most polar orange fraction. Neither azide 3 nor tetrazole 4
was identified among the remaining more mobile colorless
fractions.
In the process of developing an alternative route to 3,6-
diphenyl-1,2,4,5-thiatriazine,5 we found that tetrazine 1 is the
sole product of a nucleophilic double substitution on dichloride
2 rather than the expected azide 3 or its valence tautomer,
tetrazole 4 (Scheme 1). Here we describe the synthesis,
molecular structure, and reactivity of the unprecedented tetrazine
ylide 1. The proposed mechanism for its formation from 2 is
supported by ab initio calculations and is generalized. Finally,
we report kinetic measurements for thermolysis of ylide 1 and
discuss the mechanism and product formation in the context of
ab initio calculations.
This sequence of reagents, NaN3 followed by PrSH, was
found to be advantageous over the reverse order in which the
mercaptan is added first. Reactions of dichloride 2 with sulfur
nucleophiles show the tendency for closure of the five-
membered thiadiazole ring.6
1H NMR analysis of 1 revealed two distinct phenyl rings for
which the sets of the ortho hydrogens absorb 0.4 ppm apart
(vide infra). The molecule has some spectral characteristics of
3,6-diphenyl-1,2,4,5-tetrazine (5). The downfield absorption of
a phenyl ring (8.36 ppm) resembles that observed for 5 (8.67
ppm). The resonance at 160.53 ppm, presumably the C6 carbon
in 1 (Scheme 1), is similar to that ascribed to the C3/6 carbon in
diphenyltetrazine 5 (164.04 ppm).7 The second low-field
absorption at 145.78 ppm can be assigned to the C3 carbon in
1 and shows a marked difference in chemical environments for
the heterocyclic carbon atoms.
* Author for correspondence. Organic Materials Research Group, Depart-
ment of Chemistry, Vanderbilt University, Box 1822 Station B, Nashville,
TN 37235, Telephone/fax: (615) 322-3458. E-mail: PIOTR@
ctrvax.vanderbilt.edu.
† Vanderbilt University.
‡ University of Minnesota.
(1) 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley &
Sons: New York, 1984.
(2) Taylor, E. C.; Turchi, I. J. Chem. ReV. 1979, 79, 181-231; Huisgen,
R. Angew. Chem. Int. Ed. Engl. 1980, 19, 947-973.
(3) Groundwater, P. W.; Nyerges, M. In AdVances in Heterocyclic
Chemistry; Katritzky, A. R., Ed.; Academic Press: 1999; Vol. 73; pp 97-
129.
(4) Hegarty, A. F.; Brady, K.; Mullane, M. J. Chem. Soc., Perkin Trans.
2 1980, 535-540.
(5) Farrar, J. M.; Patel, M. K.; Kaszynski, P.; Young, V. G., Jr. J. Org.
Chem. 2000, 65, 931-940.
(6) Flowers, W. T.; Robinson, J. F.; Taylor, D. R.; Tipping, A. E. J.
Chem. Soc., Perkin Trans. 1 1981, 356-365.
(7) Farkas, L.; Keuler, J.; Wamhoff, H. Chem. Ber. 1980, 113, 2566-
2574.
10.1021/ja993884z CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/18/2000

2088 J. Am. Chem. Soc., Vol. 122, No. 9, 2000
Kaszynski and Young
Scheme 1
Table 1. Selected Experimental Bond Lengths [Å] and Angles
[deg] for 1, 6a, and Calculated for 7
Bond Lengths
1 (exp)
6a (exp)b
7 (calcd)a
S(1)-N(5)
C(1)-N(1)
C(1)-N(4)
N(1)-N(2)
N(2)-C(2)
C(2)-N(3)
N(3)-N(4)
N(4)-N(5)
S(1)-C(15)
C(1)-C(3)
C(2)-C(9)
1.6854(13)
1.296(2)
1.425(2)
1.378(2)
1.327(2)
1.342(2)
1.355(2)
1.291(2)
1.801(2)
1.481(2)
1.483(2)
1.705(10)
1.697
1.258
1.413
1.352
1.291
1.337
1.318
1.238
1.304(15)
1.324(14)
1.370(13)
1.237(14)
1.817(14)
1.488(15)
Figure 1. Thermal ellipsoid diagram of tetrazine ylide 1 with the
thermal ellipsoids drawn at 50% probability. Hydrogen atoms are given
arbitrary radii.
Angles
1 (exp)
6a (exp)b
7 (calcd)a
N(5)-S(1)-C(15)
N(1)-C(1)-N(4)
C(1)-N(1)-N(2)
C(2)-N(2)-N(1)
N(2)-C(2)-N(3)
C(2)-N(3)-N(4)
N(5)-N(4)-N(3)
N(3)-N(4)-C(1)
N(4)-N(5)-S(1)
95.61(7)
93.7(7)
91.6 (NSH)
121.4
121.1
115.3
128.8
114.3
123.1
119.1
115.0
The 1H chemical shift (3.22 ppm) of the R CH2 in the propyl
group is about 0.5 ppm downfield from a value for a typical
sulfide and is consistent with shifts expected for alkylthiodia-
zenes8,9 (e.g.,9 2.85 ppm in CH3S-NdN-Ar vs 2.60 ppm in
CH3S-Ar).
Molecular and Crystal Structures for 1. X-ray analysis of
a monoclinic crystal of 1 revealed a nearly planar substituted
tetrazine ring as shown in Figure 1.10 Selected bond lengths
and angles for 1 are shown in Table 1.
119.70(14)
121.67(13)
115.98(13)
127.28(14)
115.10(13)
119.11(12)
120.22(13)
112.10(10)
118.0(10)
114.5(9)
115.9(10)
117.8(9)
Angles
1 (exp)
6a (exp)b
7 (calcd)a
The tetrazine ring in 1 is nearly planar with the largest
deviation from the plane by 2.7(2)° observed for the
N(2)C(2)N(3)N(4). The sum of the intra-ring angles is 719.95-
(13)°, which is indistinguishable from the 720° required for a
planar hexagon. The tetrazine ring, however, exhibits a signifi-
cant in-plane distortion from the geometry observed in 2,6-
diphenyl-1,2,4,5-tetrazine11 (5) and other phenyl derivatives of
1,2,4,5-tetrazine.12,13 The shortest observed C-N bond in 1 is
1.296(2) Å for C(1)-N(1) and the longest is 1.425(2) for C(1)-
N(4), while the C-N distance in the tetrazine derivatives is
about 1.34 Å. The short C-N bond is a full double bond (cf.
1.281 Å for CdN in oximes),14 and the long one a single C-N
bond (cf. 1.431 Å for C-N in azoarenes).14 The two N-N
distances in 1, 1.378(2) Å and 1.355(2) Å, are longer than a
typical value of about 1.32 Å found in phenyltetrazines,11-13
indicative of high single bond character.14
N(1)-C(1)-N(4)-N(3)
C(2)-N(3)-N(4)-C(1)
C(1)-N(4)-N(5)-S(1)
a Gas phase calculation (HF/6-31+G*) at the Cs symmtery. b Bed-
does, R. L.; Mills, O. S. J. Chem. Res. (M) 1981, 5, 1701-1711.
-0.1(2)
-2.1(2)
0.0
0.0
180.0
179.58(10)
The propanesulfenimido group adopts an all-trans conforma-
tion and is nearly coplanar with the tetrazine ring. The largest
deviation is observed for the propyl group, which forms a
dihedral angle with the ring of 6°. In comparison with the
endocyclic N-N bonds, the exocyclic N-N bond is rather short,
and its length of 1.291(2) Å is indicative of a conjugated double
bond (cf. 1.255 Å for NdN in azoarenes).14 The S(1)-N(5)
and C(15)-S(1) distances (1.6854(13) Å and 1.801(2) Å,
respectively) are typical for the corresponding single bonds.
Thus, the fragment C3H7-S(1)-N(5)-N(4)-N(3) is more
properly described as 1-propylthiotriazene group with the N(4)
lone pair coordinating the electron-deficient carbon atom C(1).
Indeed, molecular dimensions of this fragment in 1 correspond
well to the analogous values found in the planar 6a15 and 6b16
(Table 1).
(8) Fourrey, J.-L.; Henry, G.; Jouin, P. NouV. J. Chem. 1978, 2, 397-
399.
(9) Lerch, U.; Moffatt, J. G. J. Org. Chem. 1971, 36, 3861-3869.
(10) Crystal data for 1: C17H17N5S monoclinic, P21/n, a ) 6.8294(4)
Å, b ) 13.6781(9) Å, c ) 17.5898(12) Å, â ) 90.666(1)°, V ) 1643.0(2)
Å3, Z ) 4, T ) 173 (2) K, λ ) 0.71073 Å, R (F2) ) 0.0323 (for 2176
reflections with I > 2σ(I)), R(F2) ) 0.0498 (for all data, 2895 reflections).
For details see Supporting Information.
(11) Ahmed, N. A.; Kitaigorodsky, A. I. Acta Crystallogr. 1972, B28,
739-742.
(12) Antipin, M. Y.; Timofeeva, T. V.; Yufit, D. S.; Sauer, J. Russ. Chem.
Bull. 1995, 44, 2337-2345.
(13) Breu, J.; Range, K.-J.; Biedermann, N.; Schmid, K.; Sauer, J. Acta
Crystallogr. 1996, C52, 936-940.
(14) Allen, F. H.; Kennard, O.; Watson, D. G.; Brammer, L.; Orpen, A.
G.; Taylor, R. J. Chem. Soc., Perkin Trans. 2 1987, S1-S19.
The solid-state geometry of the heterocyclic ring in 1 is
consistent with the results of gas-phase ab initio calculations

Synthesis and Structure of a Tetrazine Ylide
J. Am. Chem. Soc., Vol. 122, No. 9, 2000 2089
Figure 3. Electronic absorption spectrum for tetrazine ylide 1 recorded
in cyclohexane.Vertical lines represent the ZINDO-calculated major
transitions scaled by 4.1 × 104.
Figure 2. (a) NBO-calculated Wiberg bond order indices, (b) orbital
hybridization, and relative atomic charges for (c) the parent ylide 7
and (d) the tetrazine 8. Full circles represent negative charge density,
and dashed lines represent partial double bonds.
a small positive charge which results from the formation of the
dative bond between its lone electron pair and C(1) atom. The
negative charge is delocalized mainly on the electronegative
adjacent nitrogen atoms N(3) and N(5) and the conjugated N(2)
atom. This is again in contrast to tetrazine 8 in which the C-N
bonds are polarized to a much lower degree than those in 7
(Figure 2d).
The Electronic Absorption Spectrum of 1. The UV
spectrum of tetrazine ylide 1 consists of three bands at 368,
274, and about 200 nm, and a broad absorption band tailing to
about 510 nm, which is responsible for the orange-yellow color
of the compound (Figure 3). This spectrum is markedly different
from that of 2,6-diphenyl-1,2,4,5-tetrazine (5), which exhibits
a weak transition at 544 nm (MeOH) in addition to a strong
band at 294 nm.7
According to ZINDO calculations for 1, the long wavelength
absorption at 368 nm results from the HOMO-LUMO transi-
tion, involving mainly the sulfenimidotetrazine π electron
manifold, and HOMO-LUMO+1 transition, which includes the
π* orbital extending over the three rings as shown in Figure 4.
The FMOs of 1 are qualitatively identical to those calculated
for the parent ylide 7 (see Supporting Information).
The lowest-energy transition for 1 involving the nitrogen lone
pairs is calculated to occur at 352 nm. The same absorption for
2,6-diphenyltetrazine (5) is found7 at 544 nm and calculated at
498 nm.
The strong absorption band at 274 nm is a combination of
electronic transitions involving mainly electrons of nitrogen
atom lone pairs and the phenyl rings excited to the imidotet-
razine π* orbitals. High-energy transitions in the region of 200
nm are solely due to phenyl ring π-π* transitions.
Mechanism of Formation of Ylide 1. The formation of 1
instead of the expected product 3 or its valence tautomer 4 in
a sequence of reactions from dichloride 2 is unexpected. This
result is particularly surprising, considering that the observed
product 1 is predicted to be thermodynamically less stable by
27 kcal/mol than the product of nucleophilic substitution at the
imidoyl carbon 3, based on calculations for the parent species
(vide infra).
for the parent ylide 7 (Table 1). Geometry optimization of 7
shows a planar structure of the ylide (Cs symmetry) with
significantly alternating intra-ring bond lengths. The largest
differences between the calculated and experimental values are
observed for the C(1)-N(1), C(2)-N(2), and N(3)-N(4) bond
lengths (about 0.04 Å) and associated angles (about 2°).
The C(3)-C(8) and C(9)-C(14) phenyl rings are planar and
are twisted with respect to the tetrazine plane by 38° and 15°,
respectively. These relatively large dihedral angles are rather
unusual for phenyl derivatives of tetrazine, which are typically
coplanar in the solid state.11,13 The large dihedral angle formed
by the former phenyl ring presumably results from steric
interactions between H(8)‚‚‚N(5) separated only by 2.416 Å.
This is less than the value of 2.59 Å typically observed for the
nonbonding H‚‚‚N in organic crystals17 including phenyltetra-
zines (2.53 Å).12 The lack of coplanarity of the two rings disrupts
the intermolecular π-π stacking and allows for the other phenyl
ring to twist with respect to the tetrazine ring leaving the ortho
hydrogen atoms in 2.55 and 2.425 Å distances from the nitrogen
atoms.
In the crystal, molecules are parallel within stacks and
antiparallel between the stacks. No significant intermolecular
close contacts have been observed.
Electronic Structure of 1. The observed bond length
alternation in 1 is consistent with the results of NBO18 analysis
1
of the parent A′ ylide 7 (Figure 2). The Wiberg bond order
indices (WBOI) for 7 show that the tetrazine ring has three
single bonds, C(1)-N(4) and two N-N bonds (WBOI ) 0.95-
1.17), a nearly complete double bond, C(1)-N(1) (WBOI )
1.78), and two partial double bonds formed by the C(2) amidinyl
carbon (Figure 2a). This is in sharp contrast to results for
tetrazine 8 (WBOI ≈ 1.45; Figure 2d) and indicates that the
heterocyclic ring in 1 has non-aromatic character.
The calculated charge distribution in 7 (Figure 2c) is
consistent with the ylide structure. The N(4) nitrogen atom has
The initial reaction of the dichloride 2 with sodium azide is
well documented in the literature and yields mono-(9-Z,Z) and
di-imidoyl azides at ambient temperature.19-21 At higher tem-
(15) Beddoes, R. L.; Mills, O. S. J. Chem. Res. (M) 1981, 5, 1701-
1711.
(16) L’abbe´, G.; Willcox, A. Bull. Soc. Chim. Belg. 1979, 88, 107-
108.
(17) Rowland, R. S.; Taylor, R. J. Phys. Chem. 1996, 100, 7384-7391.
(18) Glendening, E. D.; Reed, A. E.; Carpenter, J. E.; Weinhold, F. NBO,
Version 3.1.
(19) Stolle´, R.; Netz, A. Chem. Ber. 1922, 55, 1297-1305.
(20) Stolle´, R.; Kramer, O.; Schick, E.; Erbe, H. J. Prakt. Chem. 1933,
137, 327-338.

2090 J. Am. Chem. Soc., Vol. 122, No. 9, 2000
Kaszynski and Young
Figure 4. Representation of molecular orbitals calculated (ZINDO) for ylide 1 at the crystallographic coordinates: (a) the HOMO, (b) LUMO, and
(c) the LUMO + 1.
Scheme 2
peratures, however, the imidoyl nitrogen atom undergoes
isomerization to the E-isomer 9-E,Z, which quickly cyclizes to
tetrazole 10 (Scheme 2). The rate of the Z-E isomerization
has been determined for similar compounds to be about 10-5
s-1 at 70 °C with an activation energy of about 25 kcal/mol.4
Since the reaction of 2 with NaN3 was conducted at ambient
temperature, the formation of tetrazole 10 was slow and the
mixture contained mostly the acyclic azide 9-Z,Z.
amines.22 A subsequent intramolecular nucleophilic addition of
the nitrogen lone pair to the electron-deficient nitrile carbon
atom forms the six-membered ring of 1. This mode of ring
closure is favorable, according to Baldwin’s rules,23 and
represents a rare example of a “6-endo-dig” ring closure.24,25
The NBO analysis and experimental molecular structure for 1
support this mechanism, showing a single C-N bond formed
with the nitrogen electron lone pair (vide supra).
The reaction of the azide 9-Z,Z with a thiolate anion may
proceed via three different pathways (Scheme 2): (i) nucleo-
philic displacement of the chloride and the formation of 3, (ii)
nucleophilic displacement of the azide and the formation of 11,
or (iii) nucleophilic addition to the azido group. The reaction,
based on the molecular structure of 1, must proceed according
to path iii, and the thiolate anion must add to the terminal
nitrogen atom of the N3 group. The resulting intermediate 12
easily loses a chloride anion, forming nitrile imine 13 in accord
with the general reactivity of hydrazonoyl chlorides with tertiary
It is also conceivable, although less likely, that ylide 1 is
formed directly from the adduct 12 by a “6-endo-trig” cycliza-
(22) Caramella, P.; Gru¨nanger, P. In 1,3-Dipolar Cycloaddition Chem-
istry; Padwa, A., Ed.; Wiley & Sons: New York, 1984; Vol. 1; pp 291-
392 and references therein.
(23) Baldwin, J. E. Chem. Commun. 1976, 734-736.
(24) Johnson, C. D. Acc. Chem. Res. 1993, 26, 476-482 and references
therein.
(25) Jung, M. E. In ComprehensiVe Organic Organic Transformations;
Trost, B. M., Fleming, I., Eds.; Pergamon: New York 1991; Vol 4; pp
41-52; Regan, A. C. In ComprehensiVe Organic Functional Group
Transformations; Katritzky, A. R., Meth-Cohn, O., Rees, C. W., Eds.;
Pergamon: New York 1995; Vol. 1; pp 547-549 and references therein.
(21) Behringer, H.; Fischer, H. J. Chem. Ber. 1962, 95, 2546-2556.

Synthesis and Structure of a Tetrazine Ylide
J. Am. Chem. Soc., Vol. 122, No. 9, 2000 2091
Figure 5. Optimized (HF/6-31+G*) geometries of the ground state and transition state structures, and pre- and post-transition complexes involved
in (a) the nucleophilic substitution at the imidoyl carbon, (b) nucleophilic addition to the azido group, and (c) thermolysis of the ylide 7.
tion and substitution of the imidoyl chloride. Alternatively, anion
12 or nitrile imine 13 could undergo a “5-endo” ring closure to
form the five-membered ring of triazole 14. The triazole is more
thermodynamically stable than 1 by 31 kcal/mol, based on
calculations for the parent species, but is not observed. The “5-
endo-trig” reaction of 12 is disfavored,23 and the formation of
the triazole 14 from 13 requires an initial Z-E isomerization
of the CdN bond, whose activation energy barrier is expected
to be similar to that measured for 9.
for the formation of the expected (3) and the observed (1)
products (Scheme 2). For simplicity, the substituents in ground-
state and transition-state structures were replaced with hydrogen
atoms (Figure 5). The results of ab initio calculations are
collected in Table 2, and two potential energy curves for
combined individual reactions are shown in Figure 6.
Imidoyl azide 15 and hydrogen sulfide are initially separated
by infinite distance (G298 ) -1207.138401 au, ∆G ) 0 kcal/
mol). Deprotonation of the latter generates a hydrosulfide anion
(∆G ) 347.4 kcal/mol, experimental26 344.9 kcal/mol), which
Since 1 is not the thermodynamic product, its formation must
result from more favorable reaction kinetics. Support for this
assertion is provided by the gas-phase reaction path calculation
(26) Gal, J.-F.; Maria, P.-C. In Progress in Physical Organic Chemistry;
Taft, R. W., Ed.; Wiley & Sons: New York, 1990; Vol. 17; pp 159-238.

2092 J. Am. Chem. Soc., Vol. 122, No. 9, 2000
Kaszynski and Young
Figure 6. HF/6-31+G* Gibbs free-energy profiles (298 K) for the formation of tetrazine ylide 7 (solid line) and the imidoyl azide 20 (dashed line)
in the gas phase. Transition- and ground-state structures are shown in Figure 5.
Table 2. Calculated (HF/6-31+G*) Relative Free Energies
(kcal/mol) for Species Found on Potential Energy Surfaces in Figure
6 and Shown in Figure 5a
12.8 kcal/mol of activation energy. The C-Cl bond in 22 is
elongated by 2% relative to the azide 15, which coincides with
0.1 e increase of the negative charge on chlorine.
The subsequent elimination of the chloride anion from 22
through the transition state 23 leads to the formation of the
planar post-transition complex 24. The overall two-step reaction
from pre-transition complex 17 to 24 is thermoneutral and
requires a total of ∆Gq ) 15.7 kcal/mol of activation energy.
This is over 6 kcal/mol less than the activation energy for the
nucleophilic displacement at the imidoyl carbon.
The protonation of the Cl- anion in the post-transition
complex 24 and removal to infinite distance as HCl (Et3N‚HCl
in the reaction) yields nitrile imine 25. The subsequent intramo-
lecular cyclization of nitrile imine 25 through transition state
26 to form tetrazine 7 requires a small activation energy ∆Gq
of about 14 kcal/mol and provides thermodynamic stabilization
of 24.7 kcal/mol with respect to the nitrile imine 25. Closure
of the five-membered ring in nitrile imine 25 to form triazole
27 would provide an additional 31.2 kcal/mol of stabilization
energy but is prevented by an energy barrier for the CdN double
bond isomerization.
An alternative route to ylide 7 by direct cyclization of anion
22 includes a high-energy transition state represented by the
nonplanar 28 (∆Gq ) 37.6 kcal/mol). Therefore, the involvement
of 28 in the formation of 1 is unlikely.
All intermediates and transition-state structures in the se-
quence from 15 to 7 are planar except for 21 and 22, which
exhibit small deviations from planarity. The progressive changes
in the molecular geometries of the intermediates are shown in
Figure 5.
compd
∆G298 (∆Gq
)
298
15 + H2S
15 + HS-
0
347.4
Formation of ylide 7
17
347.3
21 (TS)
22
23 (TS)
28 (TS)
24
360.1 (+12.8)
351.0
363.0 (+12.0)
388.6 (+37.6)
347.4
25 + HCl
26 (TS) + HCl
7 + HCl
48.3
62.4 (+14.1)
23.6
Formation of azide 20
16
343.6
18 (TS)
19
20 + HCl
365.5 (+21.9)
312.4
-3.7
Formation of triazole 27
-7.6
27 + HCl
a Full computational results are listed in the Supporting Information.
is allowed to interact with 15. This leads to two shallow pre-
transition minima in which the nucleophile assumes a coplanar
orientation favorable for the addition to the imidoyl carbon (16)
or to the azide (17). Both pre-transition structures are planar,
and the energy of the former is lower than that of the latter by
about 4 kcal/mol.
The subsequent nucleophilic substitution at the imidoyl carbon
proceeds in one step through the tetrahedral transition state 18
(Figure 5a) and requires activation energy ∆Gq ) 21.9 kcal/
mol. The resulting post-transition minimum, represented by 19,
is more stable than the pre-transition structure 16 by about 31
kcal/mol. Further stabilization is achieved by protonation of the
Cl- anion and separation of HCl from the product 20 to infinite
distance. The overall transformation from 15 to 20 results in a
net thermodynamic gain of about 4 kcal/mol.
The nucleophilic addition to the azido group and elimination
of the chloride anion is a more complex, two-step process and
is thermodynamically less favorable overall. The hydrosulfide
anion adds to the terminal nitrogen atom and, through the
transition state 21, forms the intermediate anion 22 (Figure 5b).
The reaction is endoergic by 3.7 kcal/mol and requires ∆Gq )
The shape of the potential-energy surfaces in Figure 6 is a
consequence of the gas-phase environment of the calculated
reactions.27,28 Since both reaction pathways involve isomeric
species, computational errors should be minimized, and a
meaningful comparison of pairs of individual reactions can be
made. For the same reason, the nonspecific solvation of the
organic species by THF should be approximately similar, and
hence the gas-phase thermodynamic calculations for the reac-
tions should be at least a semi-quantitative representation of
the relative energetics of solution processes. In contrast, an
assessment of the overall thermodynamics for the transformation
(27) Riveros, J. M.; Jose, S. M.; Takashima, K. In AdVances in Physical
Organic Chemistry; Gold, V., Bethell, D., Eds.; Academic Press: New York,
1985; Vol. 21; pp 206-219.
(28) Shi, Z.; Boyd, R. J. J. Am. Chem. Soc. 1989, 111, 1575-1579.

Synthesis and Structure of a Tetrazine Ylide
J. Am. Chem. Soc., Vol. 122, No. 9, 2000 2093
Scheme 3
This scheme for preparation of 1 can, in principle, be extended
to other structures, but the choice for the initial reagents appears
rather limited. 1,4-Dichloro-2,3-diazabutadienes belong to a rare
class of compounds suitable to serve as the L′-defg-L component
I in Figure 7. There are two readily available stable 1,3-dipole
anions, azide and diazomethyl29 anions, that can be used as the
abc anion II in the reaction. This combination of these reagents
leads to tetrazine ylides, such as 1, and may provide access to
1,2,4-triazine derivatives when CHN2(-) is used.
A much wider variety of nucleophilic reagents Nu- could
be expected to work in the sequence of the reactions in Figure
7. Besides thiolates, a number of C- and N-nucleophiles readily
add to the azide or to the diazoalkyl groups, but the products
are isolated only when the adduct can be kinetically or
thermodynamically stabilized.30,31
Figure 7. Generalized mechanism for the formation of 1.
of 15 to 7 or to 20 is much more difficult to quantify than the
individual reactions. The inorganic acids, HCl and H2S, exhibit
differential solvation and specific interactions with Et3N which
result from the difference in the gas-phase acidity (calcd 22.6
kcal/mol, experimental26 17.0 kcal/mol) among other factors.
With correction for the difference in the acidity alone, the
formation of ylide 7 from 15 is almost thermoneutral with
respect to the starting materials, while the formation of 20
become exoergic by 26.3 kcal/mol.
Reactivity of 1. Tetrazine ylide 1 can be viewed as a 1,7-
dipole and also as a formal adduct of thionitrene to tetrazine 5.
Therefore, cleavage of the exocyclic N-N bond should be
observed, and 1 should react with typical dipolarophiles.
Thermolysis. Despite the low decomposition temperature of
the neat solid (102-103 °C), thermolysis of ylide 1 in boiling
chlorobenzene was slow. In 1,2-dichlorobenzene, a higher
boiling solvent, the decomposition proceeded at an appreciable
rate. Tetrazine 5 and dipropyl disulfide were the dominant
products and were easily identified by the characteristic red-
pink color and the NMR spectra. Preparative scale thermolysis
of 1 gave tetrazine 5 in 88% isolated yield (Scheme 3).
Thermolysis of 1 was monitored by 1H NMR, showing very
clean transformation of the ylide to tetrazine 5 (Figure 8). On
the basis of the ratio of the resulting tetrazine 5 to starting ylide
1, the decomposition of 1 in o-C6D4Cl2 at 150 °C appears to be
a first-order reaction with the rate k ) 1 × 10-5 s-1 (see
Supporting Information).
The observation of tetrazine 5 and dipropyl disulfide in the
reaction mixture suggests the intermediacy of propylsulfenylni-
trene 29, which presumably dimerizes to form diazene 30
(Scheme 4). In this scenario, the initially formed tetrazine 5
and nitrene 29 are in equilibrium with ylide 1, but the
dimerization of the nitrene and the irreversible formation of
diazene 30 shifts the reaction to the right. The diazene
subsequently thermally decomposes under the reaction condi-
tions to form the disulfide in about 50% yield, according to the
NMR analysis. Alternatively, the nitrene 29 may attack the
exocyclic nitrogen atom in ylide 1 to form the transient 31,
which subsequently would undergo elimination of tetrazine 5
and form diazene 30. The latter mechanism would be consistent
with general electrophilicity of the nitrene and the proposed
path of disulfide formation during oxidative generation of
sulfenylnitrenes.32
Generalized Mechanism. The formation of the tetrazine ylide
1 can be presented as a sequence of general reactions shown in
Figure 7. In the first step, a conjugated four-atom chain defg of
I is extended to a seven-atom 1,7-dipole III via a nucleophilic
substitution of the leaving group L′ with a 1,3-dipole anion abc
(-) (II). In the formation of 1, the former represents dichloride
-
2, and the latter is the N3 anion. Addition of a nucleophile,
Nu-, to the 1,7-dipole III triggers the lone-pair-assisted
departure of the second leaving group L and the net 1,5-
transposition of the formal positive charge from b to f and
formation of IV. Both conjugated dipoles, III and IV, may
undergo “6-endo-dig” ring closure, accompanied by the net 1,5-
transposition of the formal positive charge, and formation of
cyclic conjugated dipoles V and VI, respectively. In these
reactions the unshared electron pair of the n-orbital on f or b
serves as a nucleophile, creating a new σ bond in V and VI,
respectively. Alternatively, non-polar five-membered products
VII (e.g., 10) and VIII (e.g., 14) can be formed after isomer-
ization of the d ) e or c ) d bonds, respectively, followed by
“5-endo-dig” ring closure.
The formation of the more thermodynamically stable non-
polar five-membered rings (e.g., 27 in Figure 5b) is controlled
by the height of the activation barrier for double bond isomer-
ization, while the choice between the two six-membered rings,
V and VI, depends on their relative thermodynamic stability.
Thus, the successful formation of VI (e.g., 1) requires (i) the
presence of a lone pair on atom f (nitrogen atom in 2), (ii)
Z-configuration on the d ) e and c )d double bonds in III and
IV to prevent five-membered ring closure, (iii) stable intermedi-
ate III, (iv) significant activation barriers to Z-E isomerization
in the 1,7-dipoles, and (v) lower thermodynamic stability of V
with respect to III and VI.
(29) Regitz, M.; Maas, G. Diazo Compounds. Properties and Synthesis;
Academic Press: New York, 1986; pp 437-446.
(30) Sheradsky, T. In The Chemistry of the Azido Group; Patai, S., Ed.;
Wiley & Sons: New York, 1971; pp 331-395.
(31) Engel, A. In Organische Stickstoff-Verbindungen I; Klamann, D.,
Ed.; Thieme: New York, 1990; Vol. E16a/II.; pp 1182-1237.
(32) Atkinson, R. S.; Judkins, B. D. J. Chem. Soc., Perkin Trans. 1 1981,
2615-2619.
These conditions are satisfied in the synthesis of 1 in which
the addition of the thiolate to III is stereospecific.

2094 J. Am. Chem. Soc., Vol. 122, No. 9, 2000
Kaszynski and Young
Scheme 4
Table 3. Relative Free Energies (kcal/mol) Calculated (HF/
6-31+G*) at 150 °C for Species Shown in Figure 5ca
compd ∆G423
7
0
33.1
4.4
32 (TS)
8 + 33
8 + 1/2 34
-29.6
a Full computational results are listed in the Supporting Information.
If the proposed mechanism is correct and nitrene 29 is indeed
produced in thermolysis of 1, then ylide 1 and analogous
compounds may provide a convenient alternative source of
sulfenylnitrenes34,35 and other nucleophilic nitrenes.36
Conclusions
Ylide 1 is a remarkable structure which can be described as
an intramolecular donor-acceptor adduct in a linear conjugated
chain rather than a derivative of heteroaromatic tetrazine. This
view is consistent with the results of X-ray analysis and ab initio
calculations.
The formation of ylide 1 instead of the expected product 3
has been attributed to the more favorable kinetics in the former.
Gas-phase ab initio calculations are consistent with the experi-
mental results and show that the difference between the two
reaction pathways is about 6 kcal/mol.
Furthermore, the formation of 1 is controlled by the cis
geometry of the substrate and the stereoelectronics of the
nucleophilic addition to the 1,7-dipole. The addition triggers
the formation of a new conjugated 1,7-dipole, which cyclizes
to form the six-membered ring in 1. Generalization of this
mechanism could extend this new reaction to other nucleophiles
and to at least one other heterocyclic ring.
The thermolysis of 1 proceeds with first order kinetics and
cleanly yields diphenyltetrazine 5. One possible mechanism
accounting for this reaction involves heterolytic cleavage of the
exocyclic N-N bond in 1 and formation of a nitrene in the
rate-determining step. This proposal is consistent with the results
Figure 8. Low-field portion of NMR spectra of the thermolysis reaction
mixture taken in C6D4Cl2 at three time intervals. The top spectrum
represents starting ylide 1, and the increasing absorption at 8.34 ppm
is due to the forming tetrazine 5.
According to these mechanisms, the cleavage of the N-N
bond and the formation of the nitrene is assumed to be the rate-
determining step, and nitrene dimerization, either direct or
through adduct 31, is a much faster process (k1 , k3, k4, k5 in
Scheme 4).
Ab initio calculations for the parent ylide 7 support the
proposed mechanism. The heterolytic cleavage of the exocyclic
N-N bond in ylide 7 proceeds via transition state 32 and
requires ∆Gq ) 33.1 kcal/mol of activation energy (Figure 5c
1
and Table 3). The formation of tetrazine 5 and the singlet A′
nitrene 3333 is endoergic by 4.4 kcal/mol, but the subsequent
exoergic dimerization of the nitrene 33 to diazene 34 shifts the
equilibrium to the right. The formation of the adduct 35 in the
alternative mechanism for formation of diazene 34 is signifi-
cantly endoergic by 27.0 kcal/mol and, perhaps, can be excluded.
(34) Atkinson, R. S.; Judkins, B. D.; Khan, N. J. Chem. Soc., Perkin
Trans. 1 1982, 2491-2497.
(35) Michida, T.; Sayo, H. Chem. Pharm. Bull. 1994, 42, 27-30.
(36) Deyrup, J. A. In Small Ring Heterocycles; Hassner, A., Ed.; Wiley
& Sons: New York, 1983; Vol. 1; pp 62-69.
(33) The 1A′ nitrene 33 used in this discussion is calculated to be more
stable than the corresponding 3A′′ triplet by 4.9 kcal/mol: Watts, J. D.;
Huang, M.-J. J. Phys. Chem. 1995, 99, 5331-5335.

Synthesis and Structure of a Tetrazine Ylide
J. Am. Chem. Soc., Vol. 122, No. 9, 2000 2095
of methylene chloride and deposited on a silica gel plug. The plug
was eluted with a 2:1 hexanes-methylene chloride mixture to give
260 mg of a yellowish solid. Further washing of the plug with pure
methylene chloride eluted an orange band which gave 260 mg of an
oil containing largely the ylide 1. Recrystallization of the oil from
of ab initio calculations. Clearly, further studies and trapping
experiments are necessary to support this mechanisim and to
account for the formation of the tetrazine.
Computational Methods
1
hexanes gave orange crystals: mp 102-103 °C dec; H NMR (400
MHz) δ 1.09 (t, J ) 7.03 Hz, 3H), 1.82-1.93 (m, 2H), 3.22 (t, J )
7.2 Hz, 2H), 7.35-7.59 (m, 6H), 8.06 (dd, J1) 7.8 Hz, J2) 1.6 Hz,
2H), 8.36 (dd, J1) 7.7 Hz, J2) 1.7 Hz, 2H); 13C NMR δ 13.14, 23.07,
38.93, 127.80, 128.10, 128.54, 128.86, 129.14, 131.19, 131.77, 132.40,
145.78, 160.53; IR 3065, 2963, 1603, 1531, 1473, 1405, 1365, 1213,
691 cm-1; UV (cyclohexane), λmax (log ꢀ) 368 (4.18) and 273 (4.42)
nm. Anal. Calcd for C17H17N5S: C, 63.13; H, 5.30; N, 21.65; S, 9.91.
Found: C, 63.01; H, 5.29; N, 21.61; S, 9.84. Ylide 1 exhibits limited
stability to silica gel. Substantial losses were noticed on fine 400-230
mesh gel and 100-60 mesh gel is recommended.
Ab initio calculations were carried out at the HF/6-31+G* level of
theory using the Gaussian 9437 package on SGI R8000 workstation,
and the resulting energies are listed in Supporting Information.
Appropriate symmetry constraints were used in geometry optimizations.
Harmonic vibrational frequency analyses were performed for all
stationary points. Zero-point vibrational energies (ZPE) and thermo-
dynamic properties at 298 K were calculated using 0.9135 scaling
factor.38 Transition states were obtained using the TS keyword, and
their connectivites to the appropriate minima were verified with the
IRC calculation at the HF/3-21G*. ZINDO calculations were performed
for 1 in the Cerius2 suite of programs using crystallographic atomic
coordinates.
1,4-Dichloro-1,4-diphenyl-2,3-diaza-1,3-butadiene (2). It was ob-
tained in 63% yield by chlorination of benzaldazine in CCl4 at 50 °C,
according to a literature procedure:39 mp 117-119 °C (lit.39 121-122
1
°C); H NMR δ 7.45-7.54 (m, 6H), 8.12-8.15 (m, 4H); 13C NMR δ
Experimental Section
128.54 (2C), 131.80, 133.62, 144.20; EIMS, m/z, 280 (6), 278 (34),
276 (54), 243 (18), 241 (54), 138 (100), 103 (45), 77 (86).
NMR spectra were obtained on a Bruker instrument at 400 MHz
(1H spectra) and 75 MHz (13C) in CDCl3 and referenced to TMS (1H)
or solvent (13C), unless specified otherwise. IR spectra were recorded
using a Nicolet Magna 500 instrument in KBr unless specified
otherwise. Mass spectrometry was performed using a Hewlett-Packard
5890 instrument (GCMS). Elemental analysis was provided by Atlantic
Microlab, Norcross, GA. 1,2-Dichlorobenzene-d4 was purchased from
Aldrich, Milwaukee, WI, and used without further purification.
X-ray Crystallography for 3,6-Diphenyl-1-propanesulfenimido-
1,2,4,5-tetrazine (1). A crystal of the compound was attached to a glass
fiber and mounted on the Siemens SMART system for a data collection
at 173(2) K. An initial set of cell constants was calculated from
reflections harvested from three sets of 20 frames. These initial sets of
frames are oriented such that orthogonal wedges of reciprocal space
were surveyed. This produces orientation matrixes determined from
83 reflections. Final cell constants are calculated from a set of 4683
strong reflections from the actual data collection.
3,6-Diphenyl-1-propanelsulfenimido-1,2,4,5-tetrazine (1). Dichlo-
ride 2 (277 mg, 1 mmol), NaN3 (65 mg, 1 mmol) and benzyltriethyl-
ammonium chloride (15 mg) in dry THF (10 mL) were stirred at
ambient temperature overnight under dry nitrogen. NMR spectrum of
the crude mixture shows an apparent td at 8.08 ppm (J1) 8.1 Hz, J2)
1.6 Hz) in addition to signals belonging to the starting 2 in the ratio of
2:1. The presumed diazide (dd at 7.95 ppm, J1 ) 8.5 Hz, J2 ) 1.5 Hz)
constitutes about 15% of the mixture.
Thermal Decomposition of Ylide 1. Kinetic Measurements.
Tetrazine ylide 1 (7 mg) was dissolved in dry 1,2-dichlorobenzene-d4
[1H NMR δ 0.95 (t, 7.3 Hz, 3H), 1.72-1.80 (m, 2H), 3.03 (t, J ) 7.2
Hz, 2H), 7.35-7.38 (m, 3H), 7.41-7.44 (m, 3H), 8.06-8.08 (m, 2H),
8.47-8.49 (m, 2H)] and heated in a sealed NMR tube at 150 ( 1 °C
under dry nitrogen. The sample was occasionally cooled to ambient
temperature, and the ratio of the product, 3,6-diphenyl-1,2,4,5-tetrazine
[5; 1H NMR δ 7.44-7.47 (m, 3H), 8.59-8.62 (m, 2H)] to the starting
ylide 1 was monitored by 1H NMR (400 MHz). Dipropyl disulfide [1H
NMR δ 0.89 (t, J ) 7.3 Hz, 3H), 1.59-1.66 (m, 2H), 2.54 (t, J ) 7.2
Hz, 2H)] was identified as the major byproduct. The identification of
5 and the disulfide in the mixture was confirmed by NMR of the pure
compounds in the same solvent.
3,6-Diphenyl-1,2,4,5-tetrazine (5). Ylide 1 (94 mg, mmol) was
dissolved in dry 1,2-dichlorobenzene and heated at 150 °C for 2.5 days
under dry nitrogen. Volatiles were removed under reduced pressure,
and the dark red residue was purified on a Chromatotron (CH2Cl2-
hexanes, 1:1) giving 60 mg (88% yield) of 5 as red-purple needles:
mp 195.5 °C (lit.40 mp 197-198 °C); 1H NMR δ 7.62-7.66 (m, 6H),
8.65-8.69 (m, 4H) [lit.40 δ 7.77 (m, 6H), 8.8 (dd, 4H)].
Acknowledgment. This project has been supported by NSF
(CHE-9528029).
Supporting Information Available: Tables of crystal data,
structure solution and refinement, atomic coordinates, bond
lengths and angles, and anisotropic thermal parameters along
with a decomposition kinetic plot for 1, representation of FMOs
of 7, and a list of computed energies for structures discussed in
the text (PDF) and an X-ray crystallographic file in CIF format.
This material is available free of charge via the Internet at
http:/pubs.acs.org.
1-Propanethiol (76 mg, 1 mmol) and Et3N (101 mg, 1 mmol) were
added to the resulting yellow suspension, and the mixture was stirred
for 5 h under dry nitrogen. Solvents were removed under reduced
pressure, and the orange solid residue was dissolved in a small amount
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