Rapid phosphodiester hydrolysis by zirconium(IV)

Article abstract of DOI:10.1002/(SICI)1521-3773(19980803)37:13/14<1957::AID-ANIE1957>3.0.CO;2-0

A 3 x 10⁹-fold faster cleavage of DNA dinucleotide 1 to thymidine and phosphate can be achieved under mild conditions (pH 5.5, 20°C) with a zirconium(IV) complex containing tris(hydroxymethyl)aminomethane as ligand [Eq.(1)]. In view of applications of artificial DNAses to molecular biology and gene therapy, non-redox-active zirconium(IV) is an alternative to the highly efficient but reduction-sensitive cerium(IV).

Full text of DOI:10.1002/(SICI)1521-3773(19980803)37:13/14<1957::AID-ANIE1957>3.0.CO;2-0

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[10] X-ray structure determination of CuBrCu1.2TeS2: tetragonal, space
group I41/a (no. 88), a ˆ 7.297(3), c ˆ 41.882(8) Š, Vˆ 2230.1(8) Š3,
Z ˆ 16, 1calcd ˆ 4.904 g cm-3. Data collection: 2139 reflections, 998
symmetry-independent reflections (Rint ˆ 0.098), room temperature, w
scans, MoKa radiation, l ˆ 0.71073 Š, 2qmax ˆ 508, crystal dimensions
0.3 Â 0.3 Â 0.01 mm, numerical absorption correction. Structure sol-
ution: direct methods, refinement against F 2 (full matrix, JANA98[11]),
64 refined parameters, R (I > 3sI) ˆ 0.0853, wR (I > 3sI) ˆ 0.1134, R
(all reflections) ˆ 0.1319, wR (all reflections) ˆ 0.1166, GOF ˆ 2.12,
D1min/D1max
ˆ
4.97/3.42 eŠ 3. Twinning (4/mmm) was refined and
gave a volume of 8% for the second individual. From the X-ray data
neither a superstructure ordering of the TeS2 and the TeS22 units
.
Figure 3. ESR spectrum of CuBrCu1.2TeS2 at 3.5 K and 9.64281 GHz.
Table 1. ESR data of radicals with 19 valence electrons.
(both tellurium atoms on 8e) nor ordering of the copper atoms Cu4
could be derived. Further details of the crystal structure investigations
may be obtained from the Fachinformationszentrum Karlsruhe, D-
76344 Eggenstein-Leopoldshafen, Germany (fax: (‡49)7247-808-
666; e-mail: crysdata@fiz-karlsruhe.de), on quoting the depository
number CSD-408253.
g1
g2/g3
(g?)
Dg ˆ g1 g3 T [K] Ref.
.
[11] V. Petricek, JANA98, Institute of Physics, Academy of Sciences of the
Czech Republic, Prague, Czech Republic, 1997.
[12] X. Zhang, M. G. Kanatzidis, J. Am. Chem. Soc. 1994, 116, 1890.
[13] C. R. Raymond, P. K. Dorhout, Inorg. Chem. 1996, 35, 5634.
[14] P. W. Atkins, M. C. R. Symons, The Structure of Inorganic Radicals,
Elsevier, Amsterdam, 1967.
O3
2.0174 2.0025/2.0013
2.0317 2.0066/1.9975
(2.0019)
(2.0021)
0.0161
0.0342
0.0719
77
77
3.5
[20]
[17]
this work
.
SeO2
TeS2
.
2.0804 2.0085/2.0085[a] (2.0085)
[a] g2 and g3 can differ by at most 0.01.
[15] P. W. Atkins, J. A. Brivati, N. Keen, M. C. R. Symons, P. A. Trevalion,
J. Chem. Soc. 1962, 4785.
[16] W. G. Hodgson, A. Neaves, C. A. Parker, Nature 1956, 178, 489.
[17] P. W. Atkins, M. C. R. Symons, H. W. Wardale, J. Chem. Soc. 1964,
5215.
[18] P. W. Atkins, M. C. R. Symons, J. Chem. Soc. 1962, 4794.
[19] R. Ettinger, C. B. Colburn, Inorg. Chem. 1963, 2, 1311.
[20] P. W. Atkins, A. Horsfield, M. C. R. Symons, J. Chem. Soc. 1964, 5220.
[21] J. H. Lunsford, D. P. Johnson, J. Chem. Phys. 1973, 58, 2079.
[22] F. Seel, G. Schäfer, H. J. Güttler, G. Simon, Chem. Unserer Zeit 1974,
8, 65.
[23] Much larger g factor components and 63Cu/65Cu hyperfine splitting are
expected for Cu2‡ in an approximately tetrahedral environment: S.
Knapp, T. P. Keenan, X. Zhang, R. Fikar, J. A. Potenza, H. J. Schugar,
J. Am. Chem. Soc. 1990, 112, 3452.
stituted by heavier homologues with much higher spin ± orbit
coupling constants (Table 1).[14, 17] Since a major part of the
spin density of, for example, SeO2 is located at the central
.
atom, g1 and Dg are significantly higher when tellurium is
present instead of selenium. The results of the ESR inves-
tigations (Figure 3), including the considerable linewidth and
the fast relaxation, are in accord with the structural identi-
.
fication of TeS2 . Thus, a new example has been added to this
group of well-known inorganic radicals.
Experimental Section
[24] V. Lorenzen, W. Preetz, F. Baumann, W. Kaim, Inorg. Chem., in press.
CuBrCu1.2TeS2 (1) was prepared by the reaction of stoichiometric amounts
of CuBr, Cu, Te, and S in the ratio 1:1.2:1:2 in evacuated silica ampoules.
The mixture of starting materials was melted at 6008C, homogenized by
grinding, and then tempered at 3908C. Black, shiny square or rectangular
platelets were obtained together with a microcrystalline powder after 14 d.
The purity and the sample quality was checked by X-ray powder
diffraction. Microcrystalline samples with the composition CuBrCu1.2TeS2
were investigated at 3.5 K with an Bruker ESP300 X-band ESR spectrom-
eter. The composition of selected single crystals was determined by semi-
quantitative energy dispersive X-ray analysis analysis (EDX): found:
Cu:Br:Te:S ˆ 0.350:0.169:0.158:0.324 (calcd: 0.355:0.161:0.161:0.322).
Rapid Phosphodiester Hydrolysis by
Zirconium(iv)
Reina Ott and Roland Krämer*
Received: February 5, 1998 [Z11438IE]
German version: Angew. Chem. 1998, 110, 2057 ± 2059
Nonenzymatic hydrolysis of the phosphodiester backbone
of nucleic acids is an attractive research aim in molecular
biology. Bioconjugates of hydrolytically active metal com-
plexes and antisense-oligonucleotides may have important
applications as artificial restriction enzymes since they have
much greater sequence-specificitiy than their natural counter-
parts.[1] In addition, the treatment of incurable diseases by the
in-vivo silencing of the genetic code of pathogenic proteins on
the RNA or DNA level has been attempted.[2] RNA is more
susceptible to hydrolysis than DNA and various low molec-
Keywords: chalcogens
´ copper ´ EPR spectroscopy ´
radical ions ´ solid-state chemistry
[1] A. Pfitzner, E. Freudenthaler, Angew. Chem. 1995, 107, 1784; Angew.
Chem. Int. Ed. Eng. 1995, 34, 1647.
[2] E. Freudenthaler, A. Pfitzner, Z. Kristallogr. 1997, 212, 103, and
references therein.
[3] J. Fenner, Acta Crystallogr. B 1976, 32, 3084.
[4] W. Milius, A. Rabenau, Mater. Res. Bull. 1987, 22, 1493.
[5] A. Pfitzner, S. Zimmerer, Z. Anorg. Allg. Chem. 1995, 621, 969.
[6] A. Pfitzner, S. Zimmerer, Z. Anorg. Allg. Chem. 1996, 622, 853.
[7] A. Pfitzner, S. Zimmerer, Z. Kristallogr. 1997, 212, 203.
[8] A. Pfitzner, S. Zimmerer, Angew. Chem. 1997, 109, 1031; Angew.
Chem. Int. Ed. Eng. 1997, 36, 982.
[*] Priv.-Doz. Dr. R. Krämer, R. Ott
Anorganisch-Chemisches Institut der Universität
Wilhelm-Klemm-Strasse 8, D-48149 Münster (Germany)
Fax: (‡49)251-833-8366
[9] A. Pfitzner, Chem. Eur. J. 1997, 3, 2032.
E-mail: kramerr@nwz.uni-muenster.de
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1957

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ular weight cleaving agents are available for this. The efficient
hydrolysis of linear DNA[3] under mild conditions is possible
with Ceiv, a hard Lewis acid with a high charge/size ratio that
will strongly activate the phosphate group. Heterogeneous
systems (Ceiv ± hydroxide gels) are particularly efficient and
accelerate the rate of DNA cleavage up to 1011 fold at pH 7
and 308C.[4, 5a] Homogeneous Ceiv solutions also display high
reactivity. Other metal ions, for example trivalent lanthanides,
hydrolyze linear DNA either very slowly or only at high
temperature.[6] A disadvantage of Ceiv compounds in poten-
tial applications in molecular biology is their sensitivity to
reduction (formation of CeIII). While many studies on
phosphodiester hydrolysis by middle and late transition metal
ions have been reported, little is known about the d0 ions of
the early transition metals. No evidence of ZrIV compounds
having outstanding reactivity has so far been discussed.[7]
We have investigated the hydrolysis of the ªactivatedº
phosphodiester bis(p-nitrophenyl)phosphate 1. Cleavage of 1
the pH ± rate constant profile. The chemistry of aqueous ZrCl4
solutions is complicated, and governed by the formation of
cationic polynuclear polyhydroxo species.[9] Nucleophilic
attack of the Zr-coordinated hydroxide to the P atom of the
coordinated phosphodiester is likely since [Zr(OH)]3‡ species
form at a pH less than 1. The first-order rate constant (kobs) for
the reaction of 1 to the monoester p-nitrophenylphosphate
and nitrophenol was determined from the initial rate of
reaction (<10% conversion). p-Nitrophenylphosphate is
cleaved to phosphate and p-nitrophenol at a similar rate
1
(kobs ˆ 3.4  10 3 s ). In the determination of kobs for the
hydrolysis of 1 the release of p-nitrophenol from the mono-
ester was ignored.
Additionally, the cleavage rate of 1 was investigated at
various ZrCl4 concentrations. Michaelis ± Menten behavior is
observed as shown by a linear relationship between 1/v and
1/[ZrCl4] (Figure 2). From Figure 2 the cleavage rate for the
Figure 2. Relationship between the reciprocal rate (1/v) of the hydrolysis
of 1 and the reciprocal concentration of ZrCl4. Conditions: H2O, pH 3.5,
(20 Æ 0.5)8C, 2 Â 10 5 m 1. The data are average values of two measure-
ments with a reproducibility within 20%.
is monitored spectrophotometrically by the release of p-
nitrophenol in weakly acidic solutions (lmax ˆ 317 nm, e ˆ
1
10000m 1 cm ). The pH-dependence of the hydrolysis of 1
1
Zr-coordinated phosphodiester 1 (kcat ˆ 4.9  10 3 s (208C,
in the presence of excess ZrCl4 at 208C is shown in Figure 1.
pH 3.5)), and the Michaelis constant KM, whose reciprocal
1
value 1/KM ˆ 770 M corresponds to the formation constant
of the 1 ± Zr complex, were determined. Application of the
Michaelis ± Menten law implies a fast equilibration occurs in
the formation of the complex between Zr and 1. The
coordination chemistry of the zirconium(iv) ion is determined
by fast ligand-exchange kinetics.[9] To confirm this an NMR
study was performed using the less reactive dimethylphos-
phate derivative; after several hours virtually no hydrolysis
was observed. In a D2O solution containing ZrCl4 (10mm) and
dimethylphosphate (2mm) at pH 3.5 a broad CH3 signal of
coordinated dimethylphosphate (d ˆ 3.7) and a sharp signal of
small intensity for free dimethylphosphate (d ˆ 3.52) are
observed after approximately 30 s. The equilibrium ratio of
complexed to uncomplexed dimethylphosphate is in the range
expected from the stability constant of the 1 ± Zr complex.
The relative intensities of the signals remain unchanged even
after several hours. Thus, thermodynamic equilibrium is also
reached after 30 s.[10]
Figure 1. The pH-dependence of the hydrolysis of 1 in the presence of
1
2
~
&
*
5mm ZrCl4 ( ), 5mm ZrCl4 ‡ 5mm L
(
), 5mm ZrCl4 ‡ 10mm L
( ).
Conditions: H2O, (20 Æ 0.5)8C, 2 Â 10 5 m 1. The data are average values of
two measurements with a reproducibility within 20%.
Kinetic studies were carried out in unbuffered, aqueous
solutions since the metal salt solutions themselves have
sufficient buffer capacity. Maximum reactivity is observed at
pH 4; at a pH greater than 5 zirconium hydroxide is formed.
The ZrIV-mediated hydrolysis of 1 is 5 Â 108 times faster than
When substrate 1 is added in excess the initial hydrolysis
rate is still high, but a deviation from Michaelis ± Menten
behavior is apparent. For [ZrCl4] ˆ 10 4 m and [1] ˆ 4  10 4 m
at pH 3.5 and 208C the rate of p-nitrophenol release is v ˆ 6 Â
1
the spontaneous hydrolysis at pH 7 and 258C (k ˆ 10 11 s ).[8]
1
1
Conclusions on the reaction mechanism are not possible from
10 8 m s (expected: v ˆ 11  10 8 m s ). Catalytic turnover is
1958
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not observed. After the release of one equivalent of p-
nitrophenol per zirconium ion the reaction rate is very slow,
possibly because of the formation of unreactive zirconium(iv)
phosphate complexes. A noticeable decrease in the reaction
rate in the presence of excess substrate was also described for
the hydrolysis of 1 with lanthanide(iii) ions.[11]
Kinetic investigations with CeIV salts under the same
conditions are complicated by the intense UV absorption of
the metal center. Recent studies on aqueous micellar sol-
utions of CeIV and ThIV salts have confirmed that 1 is
1
hydrolyzed much faster (k ꢀ 2 Â 10 2 s at 378C) than by
Figure 3. HPLC elution profile of an aqueous solution of 2 (10 4 m) in the
presence of ZrCl4 (5mm) and L2 (10mm) after 440 h at pH (5.5 Æ 0.1) and
(20 Æ 0.5)8C. a) 2; b) thymidine; c) thymidine-3' phosphate and thymidine-
5'phosphate.
transition metal or lanthanide(iii) salts.[12] The reactivity of
ZrCl4 at 378C (kobs ˆ 1.3  10 2 s ) is comparable to those of
1
the micellar Ceiv and Thiv systems.
Carboxylate-containing ligands such as ethylenediamine-
tetraacetate (EDTA) form stable 1:1 complexes with Zriv ions
at neutral pH, but they quench reactivity.[11] In contrast, with
the amino alcohols 2,6-bis(hydroxymethyl)pyridine (L1) and
especially with tris(hydroxymethyl)aminomethane (L2) high
reactivity is retained in weakly acidic solutions. 1H NMR
spectra were recorded of
phosphate are detectable owing to rapid monoester hydrol-
ysis. At pH 3.0 and 208C, where the initial rate of the reaction
was constant at less than 15% conversion, kobs ˆ (1.4 Æ 0.3) Â
1
10 7 s . The DNA-dinucleotide 2 is converted into thymidine
and phosphate a little faster by (NH4)2Ceiv(NO3)6 (kobs
ˆ
1
2.0 Æ 0.4) Â 10 7 s ). Considering the strong temperature
dependence of the Ceiv-mediated cleavage,[4c] this value is
comparable to literature data for the hydrolysis of 2 by
homogeneous CeIV solutions.[5a]
D2O solutions containing
L1 and ZrCl4 under the
conditions of the kinetic
The ZrIV complex of L2 (5mm ZrCl4, 10mm L2) hydrolyzes 2
with kobs ˆ (2.9 Æ 0.4)  10 7 s 1 at pH 5.5 and 208C, a rate that
corresponds to a half-life of 28 days. The zirconium-mediated
hydrolysis proceeds 3 Â 109 times faster than the spontaneous
hydrolysis of the DNA ± phosphodiester linkage at pH 7 and
258C with an estimated kobs of 10 16 s 1.[8] Under physiological
conditions (pH 7.0 , 378C) we have determined kobs ˆ (1.3 Æ
experiments (pH 4.0, 5mm
ZrCl4). For L1:Zr ratios of
0.5:1 and 1:1 broad signals
of the coordinated ligand are observed at d ˆ 8.1 (py-H4), 7.3
(d, py-H3,5), and 5.6 (s, CH2) (py ˆ pyridine). At a L1:Zr ratio
of 2:1 the excess L1 does not coordinate and is present in its
protonated form (d ˆ 8.5 (py-H4), 7.9 (d, py-H3,5), and 5.0 (s,
CH2)). 1H NMR data indicate formation of a complex
containing one equivalent of L1 per zirconium ion although
oligomerization by formation of hydroxo- or alkoxo-bridged
complexes cannot be excluded. The significant decrease of the
reactivity of the complexes at high pH may be a result of
aggregation (Figure 1).
1
0.2) Â 10 7 s .
In conclusion, Zriv salts and Zriv complexes display high
reactivity toward activated and nonactivated phosphodiesters
in weakly acidic, homogeneous solution and an efficency
similar to that of Ceiv compounds. In potential applications in
molecular biology nonredox-active Zriv compounds should be
an alternative to the reduction-sensitive Ceiv ion.
The complex derived from L2 forms homogeneous solu-
tions up to pH 6 and pH 8 with one and two equivalents of L2,
respectively, while in the absence of the ligand precipitates are
formed in a ZrCl4 solution (5mm) at pH > 5.0. Addition of
one equivalent of L2 to the ZrCl4 solution causes a significant
increase in the reactivity (Figure 1), but but no further change
in the reactivity is apparent on addition of a second equivalent
of L2. This indicates formation of a 1:1 complex. Even with an
Received: October 31, 1997
Revised version: March 27, 1998 [Z11108IE]
German version: Angew. Chem. 1998, 110, 2064 ± 2067
Keywords: DNA cleavage ´ hydrolyses ´ kinetics ´ phos-
phodiester ´ zirconium
1
excess of L2 only one CH2 signal is seen in the H NMR
spectrum, a consequence of the exchange between the free
and coordinated L2 being fast on the NMR timescale. The
observation that the dialcohol 2-amino-1,3-propanediol nei-
ther prevents the formation of zirconium hydroxide precip-
itates nor affects the reactivity of the complex suggests that L2
is bound as a tridentate O,O,O-chelating ligand. Solutions of
CeIV salts are not stabilized by L1 and L2 at pH > 4.
Hydrolysis of the phosphodiester linkage in the DNA-
dinucleotide thymidylyl(3' !5')thymidine (2) by ZrCl4 (5mm)
was analyzed by quantification of the reaction products by
reversed-phase HPLC (Figure 3). While 2 is cleaved into two
equivalents of thymidine and phosphate, only trace amounts
of the intermediates thymidine 3'phosphate and thymidine 5'-
[1] M. Komiyama, J. Biochem. 1995, 118, 665 ± 670.
[2] B. Meunier, DNA and RNA Cleavers and Chemotherapy of Cancer or
Viral Diseases, Kluwer Academic, Boston, 1996.
[3] Cyclic, ªsupercoiledº-plasmid DNA is activated by intrinsic strain[1]
and is hydrolyzed by transition metal and lanthanide(iii) ions,
particularly efficiently by cobalt(iii) complexes: R. Hettig, H.-J.
Schneider, J. Am. Chem. Soc. 1997, 119, 5638 ± 5647.
[4] a) M. Komiyama, T. Shiiba, T. Kodama, N. Takeda, J. Sumaoka, M.
Yashiro, Chem. Lett. 1994, 1025 ± 1028; b) B. K. Tagasaki, J. Chin, J.
Am. Chem. Soc. 1994, 116, 1121 ± 1122; c) N. Takeda, T. Imai, M.
Irisawa, J. Sumaoka, M. Yashiro, H. Shigekawa, M. Komiyama, Chem.
Lett. 1996, 599 ± 600.
[5] a) M. Komiyama, N. Takeda, Y. Takahashi, H. Uchida, T. Shiiba, T.
Kodama, M. Yashiro, J. Chem. Soc. Perkin Trans. 2, 1995, 269 ± 274.
The radiotoxic ThIV cleaves DNA at pH 4 and 708C by about four
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1959

COMMUNICATIONS
times slower than Ceiv : T. Ihara, H. Shimura, K. Ohmori, H. Tsuji, J.
Takeuchi, M. Tagaki, Chem. Lett. 1996, 687 ± 688.
[6] EuIII accelerates the hydrolysis of DNA-dinucleotides at 708C about
3 Â 107 fold: R. Hettich, H.-J Schneider, J. Chem. Soc. Perkin Trans. 2,
1997, 2069 ± 2072. The cleavage of linear DNA by CoIII complexes has
been reported, but no kinetic data were given.
[7] Very recently, Moss et al. have reported phosphodiester hydrolysis by
ZrCl4 (R. A. Moss, J. Zhang, K. G. Ragunathan, Tetrahedron Lett.
1998, 39, 1529 ± 1532). The study is less detailed and limited to
activated substrates such as 1 and was submitted for publication more
than one month later than our manuscript. The hydrolysis of an RNA-
oligonucleotide in acetate-buffered solutions ZrCl4 is less reactive
than lanthanide(iii) compounds: J. Visscher, A. W. Schwartz, Nucleic
Acid Res. 1992, 20, 5749 ± 5752.
Scheme 1. Thermal reaction of enyne-allenes: C2 ± C6 cyclization (left) and
Myers ± Saito C2 ± C7 cyclization (right). 1: R ˆ H, 2: R ˆ Ph, 3: R ˆ tBu, 4:
R ˆ NH2; R1 ˆ R2 ˆ H.
a C2 ± C6 cyclization (Scheme 1).[4] For different groups R1 and
R2, the new C2 ± C6 cyclization takes place if the terminal
hydrogen atom of the alkyne group (R ˆ H) is replaced by an
aryl group (R ˆ Ph) or by sterically bulky groups (e.g., R ˆ
tBu, SiMe3). Later Gillmann et al.[5] and Rodriguez et al.[6]
found a similar reaction switch, which indicates that the new
C2 ± C6 cyclization constitutes a general reaction motif.
As indicated on the right-hand side of Scheme 1, the rate-
determining step of the Myers ± Saito reaction is the forma-
tion of a (s,p) biradical. Experimental studies[7, 8] on the new
C2 ± C6 cyclization (shown on the left-hand side of Scheme 1)
also suggest that biradical formation is the rate-determining
step, but the final proof for a biradical intermediate was
missing so far. Although the switch from the C2 ± C7 to the
C2 ± C6 cyclization is experimentally well established, the
reasons are still unclear.
[8] J. Chin, M. Banaszczik, V. Jubian, X. Zou, J. Am. Chem. Soc. 1989, 111,
186 ± 190.
[9] R. C. Fay in Comprehensive Coordination Chemistry, Vol. 3 (Eds.: G.
Wilkinson, R. D. Gillard, J. A. McCleverty), Pergamon, Oxford, 1987,
p364, 384 ± 387 and references therein. A. Singhal, L. M. Toth, J. S.
Lin, K. Affholter, J. Am. Chem. Soc. 1996, 118, 11529 ± 11534.
[10] Kinetic investigation of the hydrolysis of 1 by ZrCl4 was started 20 ±
30s after mixing of the reagents. The reaction rate is approximately
constant in the time interval 10 ± 60 s.
[11] H.-J. Schneider, J. Rammo, R. Hettich, Angew. Chem. 1993, 105,
1773 ± 1776; Angew. Chem. Int. Ed. Engl. 1993, 32, 1716 ± 1719.
[12] K. Bracken, R. A. Moss, K. G. Ragunathan, J. Am. Chem. Soc. 1997,
119, 9323 ± 9324.
In the present investigation quantum-chemical calcula-
tions[9] address for the first time the regioselectivity of
biradical cyclizations in enyne-allenes with different substitu-
entsÐnamely, R ˆ H (1), Ph (2), tBu (3), and NH2 (4)Ðat the
alkyne terminus (with R1 ˆ R2 ˆ H). In addition, the hitherto
postulated biradical intermediate of the C2 ± C6 cyclization
could be trapped by hydrogen transfer, thus providing the
most direct proof of its biradical nature.
Regioselectivity of Biradical Cyclizations of
Enyne-Allenes: Influence of Substituents on
the Switch from the Myers ± Saito to the Novel
C2 ± C6 Cyclization**
Bernd Engels,* Christian Lennartz, Michael Hanrath,
Michael Schmittel,* and Marc Strittmatter
The theoretical results are summarized in Table 1, and the
optimized geometrical structures of the reactants and of the
transition states are shown in Figure 1. We will first compare
The Myers ± Saito C2 ± C7 cyclization of enyne-allenes[1] has
recently received a lot of attention owing to the involvement
of the a,3-didehydrotoluene biradicals (Scheme 1) in DNA-
cleavage reactions[2] and subsequent reactions of synthetic
interest.[3]
The synthetic potential of thermal enyne-allene reactions
was extended when Schmittel and co-workers found a
complete switch from the Myers ± Saito C2 ± C7 cyclization to
Table 1. Summary of the theoretical data. Energy differences are given
with respect to the reactants (in kcalmol 1). Thermochemical corrections
were made at a temperature of 298 K.
R ˆ
H
Ph
tBu
NH2
C2 ± C7 cyclization
[c]
TS[a]
RC2±C7
DE=
DH=
DG=
2.07
22.4
21.4
24.0
2.06
28.0
26.7
29.8
2.07
2.08
[*] Priv-Doz. Dr. B. Engels, Dipl.-Chem. C. Lennartz,
Dipl.-Ing. M. Hanrath
29.0
27.9
31.1
20.9
19.8
22.7
Institut für Physikalische und Theoretische Chemie der Universität
Wegelerstrasse 12, D-53115 Bonn (Germany)
Fax: (‡49)228-73-9066
[c]
product[b]
RC2±C7
1.43
21.3
1.41
23.3
±
±
1.50
34.7
E-mail: bernd@rs5.thch.uni-bonn.de
DEr
C2 ± C6 cyclization
Prof. Dr. M. Schmittel, Dipl.-Chem. M. Strittmatter
Institut für Organische Chemie der Universität
Am Hubland, D-97074 Würzburg (Germany)
Fax: (‡49)931-888-4606
TS[a]
RC2±C6
DE=
DH=
DG=
1.90
1.96
27.2
25.1
28.7
1.90
2.13
16.9
15.4
17.8
[c]
30.8
29.0
31.4
33.0
31.4
33.3
E-mail: mjls@chemie.uni-wuerzburg.de
[c]
product[b]
RC2±C6
DEr
1.51
12.0
1.50
1.3
±
±
1.47
37.0
[**] This work was supported by the Deutsche Forschungsgemeinschaft
(SFB 344, project Schm 647/7-1) and the Fonds der Chemischen
Industrie. The services and computer time of the Computing Center of
the Universität Köln and HRLZ Jülich have been essential to the
present study.
[a] DF(B3LYP) in combination with a 6-31G* basis set. TS ˆ transition
state. [b] MR-CI in combination with a DZP basis set. [c] Distance in Š.
1960
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
1433-7851/98/3713-1960 $ 17.50+.50/0
Angew. Chem. Int. Ed. 1998, 37, No. 13/14