Ambident reactivities of methylhydrazines

Article abstract of DOI:10.1002/anie.201107315

Kinetics versus thermodynamics: Methyl groups increase the nucleophilic reactivity of the substituted position of hydrazines and reduce the nucleophilicity of the adjacent nitrogen center. As a result, the tertiary nitrogen atom of 1,1-dimethylhydrazine is 3000 times more reactive than the NH₂ group, but under thermodynamic control substitution of an NH ₂ proton occurs (see picture). Copyright

Full text of DOI:10.1002/anie.201107315

Angewandte
Chemie
DOI: 10.1002/anie.201107315
Ambident Reactivity
Ambident Reactivities of Methylhydrazines**
Tobias A. Nigst, Johannes Ammer, and Herbert Mayr*
Dedicated to Professor Gꢀnter Szeimies on the occasion of his 75th birthday
Table 1: Reference electrophiles 4 used in this study.
Reference electrophile
Hydrazines are an important class of compounds which find
considerable technical and commercial applications.[1] Fur-
thermore, numerous biological activities of hydrazine deriv-
atives have been discovered which make them potent drugs,
peptidomimetics, and pesticides.[1,2]
E[a]
4a
4b
ꢁ15.83
Besides their synthetic relevance, hydrazines are also
interesting from a mechanistic point of view, as they have two
adjacent nucleophilic nitrogen centers. Unsymmetrically
substituted hydrazines are, therefore, ambident nucleophiles,
and the factors that determine the regioselectivities of their
reactions have been studied intensively.[1] Typically, protona-
tions as well as alkylations of alkyl-substituted hydrazines
take place at the more-substituted nitrogen atom. Thus, in the
case of 1,1-dialkyl hydrazines, quaternary ammonium salts are
formed.[1,3] Kinetic investigations focused on the parent
hydrazine[4] and little is known about the nucleophilic
reactivities of substituted hydrazines[5] though this informa-
tion is crucial for predicting the regioselectivities in a variety
of heterocyclic syntheses.
ꢁ12.18
n=1
n=2
4c
4d
ꢁ10.04
ꢁ9.45
n=1
n=2
4e
4 f
ꢁ8.76
ꢁ8.22
R=N-pyrrolidino
R=NMe2
R=N-morpholino
R=N(Me)CH2CF3
4g
4h
4i
ꢁ7.69
ꢁ7.02
ꢁ5.53
ꢁ3.85
4j
To investigate the factors which control relative reactiv-
ities of the different sites of unsymmetrical hydrazines we
4k
4l
ꢁ1.36
0.00
[a] Electrophilicity parameters E from Ref. [6b,c].
The rate constants of the reactions of 1–3 with the
reference electrophiles 4b–h were determined spectrophoto-
metrically in acetonitrile at 208C using conventional and
stopped-flow methods as described elsewhere.[6] For the fast
reactions (k2 > 106 mꢁ1 sꢁ1), benzhydrylium ions 4g–k were
generated by laser-flash photolysis (7 ns pulse, 266 nm) of
substituted benzhydryl phosphonium tetrafluoroborates in
the presence of hydrazines.[7] In all cases, the hydrazines 1–3
were used in large excess (over 8 equivalents) relative to the
electrophiles to ensure first-order conditions.
Scheme 1. Structures of hydrazines 1–3.
have studied the reactions of the hydrazines 1–3 (Scheme 1)
with the quinone methides 4a,b and the benzhydrylium ions
4c–l (Table 1). The electrophiles 4 have been used as
reference compounds for the construction of comprehensive
nucleophilicity scales based on Equation (1), which character-
lg k2ð20 ꢀCÞ ¼ sNðN þ EÞ
ð1Þ
Mono-exponential decays of the absorbances of the
electrophiles were observed for all reactions with the
unsubstituted hydrazine (1), and the first-order rate constants
kobs were obtained by least-squares fitting of the exponential
izes nucleophiles by two parameters (nucleophilicity N and
the sensitivity parameter sN) and electrophiles by one param-
eter (electrophilicity E).[6]
obst
function A ¼ A0eꢁk þ C to the absorbance; a typical
[*] Dipl.-Chem. T. A. Nigst, Dipl.-Ing. J. Ammer, Prof. Dr. H. Mayr
Department Chemie, Ludwig-Maximilians-Universitꢀt Mꢁnchen
Butenandtstrasse 5–13 (Haus F), 81377 Mꢁnchen (Germany)
E-mail: Herbert.mayr@cup.uni-muenchen.de
example is shown in Figure S1 of the Supporting Information.
Plots of kobs versus the hydrazine concentrations were linear
and the second-order rate constants k2 listed in Table 2 were
obtained from the slopes of these plots [Eq. (2)]. Theoret-
ically, k0 corresponds to the sum of all first-order side
Homepage: http://www.cup.lmu.de/oc/mayr
[**] We thank the Deutsche Forschungsgemeinschaft (SFB 749) and the
Fonds der Chemischen Industrie for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201107315.
kobs ¼ k2½1ꢂ þ k0
ð2Þ
Angew. Chem. Int. Ed. 2012, 51, 1353 –1356
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1353

.
Angewandte
Communications
Table 2: Second-order rate constants k2 and k2’ for the reactions of the
reference electrophiles 4 with the primary, secondary, and tertiary amine
functions of the hydrazines 1–3 in acetonitrile at 208C.
Hydrazine
Electrophile[a]
k2 [mꢁ1 sꢁ1
]
k2’ [mꢁ1 sꢁ1
]
4b
4c
4d
4e
4e
4g
4h
4i
2.23ꢂ102[b]
3.41ꢂ103[c]
8.74ꢂ103[b]
2.04ꢂ104[b]
2.14ꢂ104[c]
1.58ꢂ105[b]
2.95ꢂ105[c]
1.22ꢂ106[c]
9.90ꢂ106[c]
4j
4b
4c
4e
4g
4h
4i
5.69ꢂ10ꢁ1
1.18ꢂ101
1.27ꢂ102
1.44ꢂ103
2.46ꢂ103
3.78ꢂ106
8.06ꢂ106
3.46ꢂ107
2.04ꢂ108
4j
4e
4 f
4g
4h
4i
6.15ꢂ102
1.26ꢂ103
3.74ꢂ103
1.17ꢂ104
3.00ꢂ106
1.81ꢂ107
4.58ꢂ108
Figure 1. a) Fast exponential decay of the absorbance at 611 nm during
the reaction of 4g (generated from [4g-PBu3]=1.47ꢂ10ꢁ5 m) with 1,1-
dimethylhydrazine ([2]=8.43ꢂ10ꢁ2 m; kobs =3.71ꢂ105 sꢁ1). b) Slow
exponential decay of the absorbance at 611 nm during the reaction of
4g ([4g]=1.80ꢂ10ꢁ5 m) with 1,1-dimethylhydrazine
4j
4k
[a] Counterion of the benzhydryl cations: BF4ꢁ. [b] Determined using a
1:2 mixture of N2H4·2HCl and 1,8-diaza-bicyclo[5.4.0]undec-7-ene.
[c] Determined using N2H4·H2O.
([2]=1.45ꢂ10ꢁ4 m; kobs =1.78ꢂ10ꢁ1 sꢁ1). Insets: Plots of kobs versus [2]
yield the second-order rate constants k2’=3.78ꢂ106 mꢁ1 sꢁ1 and
k2 =1.44ꢂ103 mꢁ1 sꢁ1
.
reactions of the benzhydrylium ions and the reverse reaction.
As it is very small compared with k2[1], it is dominated by
inaccuracies in kobs and will, therefore, not be discussed in the
following.
10ꢁ4 m 2 determined with the stopped-flow technique. Again,
a mono-exponential decay of the absorbance of the carbo-
cation was observed and a linear correlation of kobs with the
hydrazine concentration was obtained, the slope of which
yielded another significantly lower second-order rate con-
stant of k2 = 1.44 ꢀ 103 mꢁ1 sꢁ1 (Table 2).
Analogous observations were made for the reaction of 2
with 4h, where we obtained second-order rate constants of
k2’ = 8.06 ꢀ 106 mꢁ1 sꢁ1 at high concentrations of 2 and k2 =
2.46 ꢀ 103 mꢁ1 sꢁ1 at low concentrations (Table 2).
This behavior can be explained by the mechanism
depicted in Scheme 2. The fast and reversible reaction
corresponds to the attack at the tertiary nitrogen while the
slower reaction, which becomes irreversible by deprotonation
with a second molecule of the hydrazine, corresponds to the
attack at the NH2 group of 2. At low concentrations of 1,1-
dimethylhydrazine (2), the equilibrium for the fast reaction,
which leads to the kinetically controlled product, is almost
completely on the side of the starting material, and the slow
process (reaction at the NH2 group) is observed exclusively.
When we investigated the reactions of 2 with other
reference electrophiles, one of the two modes of attack was
always predominant, so that we obtained only one second-
order rate constant for each reaction: For the weak electro-
philes 4b–e, the equilibrium of the fast reaction is on the side
of the reactants and we observed only the slow decay. For the
stronger electrophiles 4i,j, we observed exclusively the fast
The situation is more complicated for 1,1-dimethylhydra-
zine (2) and trimethylhydrazine (3) which contain tertiary
amine groups. With these systems, we observed different
kinetic behavior depending on the concentration of the
hydrazines and the nature of the electrophile. For the
reactions of 2 with 4g and 4h we could even observe two
separate exponential decays on different time scales when
different concentrations of 2 were employed. Figure 1a shows
the decay of the absorbance of 4g which was generated by
laser-flash photolysis of the phosphonium salt 4g-PBu3 in
acetonitrile at 208C in the presence of 2 (8.43 ꢀ 10ꢁ2 m). A
mono-exponential decay of the absorbance of the carbocation
was observed within 15 ms (approximately 80% conversion),
while the remaining absorbance disappeared within around
100 ms. With increasing hydrazine concentrations, the con-
version arising from the fast reaction increased, and even-
tually the fast decay was observed almost exclusively. From
the linear increase of kobs with the concentration of 2, we
obtained the second-order rate constant k2’ = 3.78 ꢀ 106 mꢁ1 sꢁ1
(Table 2).
At lower concentrations of the hydrazine, the slower
decay became more dominant, and for [2] < 3 ꢀ 10ꢁ4 m, the
initial fast decay of the absorbance was almost absent and a
mono-exponential decay on a longer timescale was observed.
Figure 1b shows the decay of 4g in the presence of 1.45 ꢀ
1354
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1353 –1356

Angewandte
Chemie
Table 3: N and sN parameters of 1–3 in CH3CN.
Hydrazine
N
sN
N
sN
1
2
3
16.45[a]
0.56[a]
11.72
12.43
0.73
0.75
22.41
17.75
0.45
0.53
Scheme 2. Ambident reactivity of 1,1-dimethylhydrazine (2) in reac-
tions with 4.
[a] Nucleophilicity parameters in methanol/acetonitrile (91:9 v/v):
N=13.47; sN =0.70.[10]
reaction because the formation of the quaternary hydrazi-
nium ions is almost quantitative even at low hydrazine
concentrations (Table 2).[8]
This information is also given by the nucleophilicity
parameters N and sN in Table 3, which have been derived from
the correlations in Figure 2 and in Figure S2 (Supporting
Information). The different values of sN for the two sites in 2
and 3 imply, however, that the positional selectivities decrease
with increasing reactivity of the electrophiles.
The reaction mechanism, derived from the kinetic experi-
ments (Scheme 2) is in line with structural investigations by
NMR spectroscopy.[9] Scheme 3 shows that the quinone
methide 4a reacts exclusively with the NHMe center of 3 to
the 1:1 adduct 6a in analogy to the reaction of the parent
hydrazine 1 (!5a).
Figure 2 shows that the rate constants measured for the
parent hydrazine (1) with the three different methods all
correlate linearly with the electrophilicity parameter E as
required by Equation (1), while two correlation lines are
found for 1,1-dimethylhydrazine (2) which are assigned to the
two sites of attack. It can be seen that the methyl substituents
increase the nucleophilicity of the substituted nitrogen by
more than one order of magnitude and decrease the reactivity
of the neighboring site by more than two orders of magnitude.
An analogous behavior was found for the reactions of
trimethylhydrazine (3; Table 2). Though we did not find
systems where the two competing reactions could be observed
separately, Figure S2 in the Supporting Information clearly
shows two correlation lines, the higher one for the reaction at
the tertiary nitrogen and the lower one for the reaction at the
NHMe position. Again, methyl substitution increases the
nucleophilicity of the substituted center while it reduces that
of the adjacent nitrogen: The NHMe group of 3 is approx-
imately four-times more nucleophilic than the NH2 group in 2
(reactions with 4e–h, Table 2), while the tertiary nitrogen of 3
is 11-times less nucleophilic than the corresponding nitrogen
in 2 (reactions with 4i,j, Table 2).
Similarly, NMR spectroscopic analysis of the product
obtained from 4h and 2 showed the exclusive formation of 7h,
which arises from electrophilic attack at the NH2 group of 2
(Scheme 4).[11] In contrast to the interpretation of the kinetic
data, NMR analysis of the product obtained from 4j and 2
also showed exclusive attack at the NH2 group of 2 (!7j).[12]
We, therefore, assumed that the initial formation of the
quaternary hydrazinium ion 8j, which was derived from the
correlation in Figure 2, is followed by re-ionization and
eventual formation of the thermodynamically favored prod-
uct 7j. To confirm this hypothesis, we have also studied the
reactions of the more electrophilic benzhydrylium ions 4k
and 4l with 2. At short reaction times we observed the
predominant formation of the quaternary hydrazinium ions
8k and 8l, which subsequently rearranged to 7k and 7l,
respectively (Scheme 4).
We have thus shown that the tertiary nitrogen in 1,1-
dimethylhydrazine (2) is approximately 3000 times (!) more
reactive than the NH2 group and that methyl groups generally
activate the substituted and deactivate the adjacent nitrogen
center. In line with these conclusions, the unsymmetrical
hydrazine 2 has been reported to yield quaternary hydrazi-
Figure 2. Plots of the second-order rate constants lgk2 and lgk2’ for the
reactions of hydrazine (1) and 1,1-dimethylhydrazine (2) with benzhy-
drylium ions and quinone methides in CH3CN at 208C versus the E
parameters of 4.
Scheme 3. Products of the reactions of hydrazines 1 and 3 with 4a in
acetonitrile at 208C.
Angew. Chem. Int. Ed. 2012, 51, 1353 –1356
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
1355

.
Angewandte
Communications
Information; d) A. Raja, J. Lebbos, P. Kirkpatrick, Nat. Rev.
Drug Discovery 2003, 2, 857 – 858; e) G. Campiani et al., J. Med.
Chem. 2001, 44, 305 – 315, see Supporting Information; f) L.
Ling, L. J. Urichuk, B. D. Sloley, R. T. Coutts, G. B. Baker, J. J.
Shan, P. K. T. Pang, Bioorg. Med. Chem. Lett. 2001, 11, 2715 –
2717; g) E. S. Lightcap, R. S. Silverman, J. Med. Chem. 1996, 39,
686 – 694; h) J. Gante, Synthesis 1989, 405 – 413; i) T. Singh, J. F.
Hoops, J. H. Biel, W. K. Hoya, R. G. Stein, D. R. Cruz, J. Med.
Chem. 1971, 14, 532 – 535.
[3] a) A. Bagno, E. Menna, E. Mezzina, G. Scorrano, D. Spinelli, J.
Phys. Chem. A 1998, 102, 2888 – 2892; b) H. H. Sisler, G. M.
Omietanski, B. Rudner, Chem. Rev. 1957, 57, 1021 – 1047; c) O.
Westphal, Ber. Dtsch. Chem. Ges. 1941, 74, 759 – 776; d) C.
Harries, T. Haga, Ber. Dtsch. Chem. Ges. 1898, 31, 56 – 64.
[4] Selected examples: a) J. R. Leis, M. E. PeÇa, A. M. Rios,
J. Chem. Soc. Perkin Trans. 2 1995, 587 – 593; b) J. W. Bunting,
J. M. Mason, C. K. M. Heo, J. Chem. Soc. Perkin Trans. 2 1994,
2291 – 2300; c) C. D. Ritchie, J. Am. Chem. Soc. 1975, 97, 1170 –
1179; d) R. N. Washburne, J. G. Miller, A. R. Day, J. Am. Chem.
Soc. 1958, 80, 5963 – 5965; e) J. F. Bunnett, G. T. Davis, J. Am.
Chem. Soc. 1958, 80, 4337 – 4339.
[5] a) J. E. Dixon, T. C. Bruice, J. Am. Chem. Soc. 1971, 93, 6592 –
6597; b) T. C. Bruice, A. Donzel, R. W. Huffman, A. R. Butler,
J. Am. Chem. Soc. 1967, 89, 2106 – 2121; c) W. P. Jencks, J.
Carriuolo, J. Am. Chem. Soc. 1960, 82, 1778 – 1786.
[6] a) H. Mayr, B. Kempf, A. R. Ofial, Acc. Chem. Res. 2003, 36, 66 –
77; b) R. Lucius, R. Loos, H. Mayr, Angew. Chem. 2002, 114, 97 –
102; Angew. Chem. Int. Ed. 2002, 41, 91 – 95; c) H. Mayr, T. Bug,
M. F. Gotta, N. Hering, B. Irrgang, B. Janker, B. Kempf, R. Loos,
A. R. Ofial, G. Remennikov, H. Schimmel, J. Am. Chem. Soc.
2001, 123, 9500 – 9512; d) H. Mayr, M. Patz, Angew. Chem. 1994,
106, 990 – 1010; Angew. Chem. Int. Ed. Engl. 1994, 33, 938 – 957.
[7] J. Ammer, M. Baidya, S. Kobayashi, H. Mayr, J. Phys. Org.
Chem. 2010, 23, 1029 – 1035.
[8] For the reaction of 2 with 4j, we only observed the fast decay
(k2’ = 2.04 ꢀ 108 mꢁ1 sꢁ1) even at concentrations as low as [2] =
1.58 ꢀ 10ꢁ5 m. That we observed > 90% conversion even at such
low concentrations (only ca. sixfold excess over 4j) proves that
the large rate constants measured for 4g–j at high concentrations
of 2 do not result from impurities in the hydrazine but reflect the
nucleophilic reactivity of 2.
[9] The regioselectivities of the reactions of 2 and 3 with the
reference electrophiles were determined from the 3J couplings of
the methyl groups with the Ar2CH group in HMBC NMR
spectra (see Supporting Information).
Scheme 4. Reactions of 1,1-dimethylhydrazine (2) with 4h–l in CD3CN.
[a] Formation of 7k and 7l is accompanied by some decomposition.
nium salts in alkylations which proceed by irreversible SN2
reactions.[13] In reversible reactions, for example, acylations,
the thermodynamically more-favored product is formed,
however, which results from attack at the NH2 group and
subsequent deprotonation.[14] As shown for many other
ambident nucleophiles, the observed regioselectivity does
not depend on the hardness of the reaction partner, whereas
the reversibility of the electrophilic attack plays a decisive
role.[15]
Experimental Section
The kinetics of the reactions of the benzhydrylium ions with the
hydrazines 1–3 were monitored by UV/Vis spectroscopy. For slow
reactions (t1/2 > 10 s), the spectra were collected by using a diode-
array spectrophotometer. Stopped-flow spectrophotometer systems
were used for the investigation of faster reactions (10 ms < t1/2 < 10 s).
Reactions with t1/2 < 10 ms were analyzed by laser-flash photolytic
generation of 4g–j from phosphonium ions in the presence of excess
hydrazine. The sample solutions were irradiated with 7 ns pulses from
a quadrupled Nd:YAG laser (266 nm, 40–60 mJ/pulse). For details of
the kinetic experiments, syntheses and product characterization see
the Supporting Information.
[10] T. B. Phan, M. Breugst, H. Mayr, Angew. Chem. 2006, 118, 3954 –
3959; Angew. Chem. Int. Ed. 2006, 45, 3869 – 3874.
[11] Deprotonated 7h was isolated in 66% yield after treatment of
4h with an excess of 2 (see Supporting Information).
[12] Reaction of the less-substituted nitrogen center was also
detected in the reaction of 4j with 3 (see Supporting Informa-
tion).
Received: October 17, 2011
Published online: December 23, 2011
[13] a) S. A. Malin, B. M. Laskin, A. S. Malin, Russ. J. Appl. Chem.
2007, 80, 2165 – 2168; b) L. K. Dalton, S. Demerac, B. C. Elmes,
Aust. J. Chem. 1980, 33, 1365 – 1372; c) E. Renouf, Ber. Dtsch.
Chem. Ges. 1880, 13, 2169 – 2174; d) K.-H. Kçnig, B. Zeeh,
Chem. Ber. 1970, 103, 2052 – 2061; e) G. Pollak, H. Yellin, A.
Carmi, J. Med. Chem. 1964, 7, 220 – 224.
[14] a) G. Zinner, T. Krause, Arch. Pharm. 1977, 310, 704 – 714; b) R.
Ohme, H. Preuschhof, J. Prakt. Chem. 1971, 313, 626 – 635; c) W.
Walter, K.-J. Reubke, Chem. Ber. 1970, 103, 2197 – 2207; d) R. C.
Slagel, A. E. Bloomquist, Can. J. Chem. 1967, 45, 2625 – 2628;
e) W. G. Finnegan, R. A. Henry, J. Org. Chem. 1965, 30, 567 –
575; f) R. F. Meyer, J. Org. Chem. 1965, 30, 3451 – 3454.
[15] Review: H. Mayr, M. Breugst, A. R. Ofial, Angew. Chem. 2011,
123, 6598 – 6634; Angew. Chem. Int. Ed. 2011, 50, 6470 – 6505.
Keywords: ambident nucleophiles · correlation analysis ·
hydrazines · kinetics · linear-free energy relationships
.
[1] a) U. Ragnarsson, Chem. Soc. Rev. 2001, 30, 205 – 213, and
references therein; b) E. W. Schmidt, Hydrazines and its Deriv-
atives: Preparation, Properties, Applications, 2nd ed., VCH,
Weinheim, 2001.
[2] Selected examples: a) E. M. Nurminen, M. Pihlavisto, L. Lꢁzꢁr,
U. Pentikꢂinen, F. Fꢃlçp, O. T. Pentikꢂinen, J. Med. Chem. 2011,
54, 2143 – 2154; b) J. H. Ahn et al., Bioorg. Med. Chem. Lett.
2007, 17, 2622 – 2628, see Supporting Information; c) C. Ramesh
et al., J. Am. Chem. Soc. 2006, 128, 14476 – 14477, see Supporting
1356
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1353 –1356