Competition between Nucleophilic Substitution of Halogen (SNAr) versus Substitution of Hydrogen (SNArH) - A Mass Spectrometry and Computational Study

Article abstract of DOI:10.1002/chem.201406542

The mechanism of intramolecular gas-phase reactions of N-(2-X-5-nitrophenyl)-N-methylacetamide carbanions (X = H, F, Cl) has been studied using negative ion electrospray mass spectrometry ((-)ESI-MS) technique and modelled computationally. It was proven t

Full text of DOI:10.1002/chem.201406542

DOI: 10.1002/chem.201406542
Communication
&
Aromatic Nucleophilic Substitution
Competition between Nucleophilic Substitution of Halogen (SNAr)
versus Substitution of Hydrogen (SNArH)—A Mass Spectrometry
and Computational Study
Kacper Błaziak, Mieczysław Ma˛kosza, and Witold Danikiewicz*[a]
Abstract: The mechanism of intramolecular gas-phase re-
actions of N-(2-X-5-nitrophenyl)-N-methylacetamide car-
banions (X=H, F, Cl) has been studied using negative ion
electrospray mass spectrometry ((À)ESI-MS) technique and
modelled computationally. It was proven that all three
anions form cyclic sH adducts, which undergo elimination
of water. In the case of X=F, formation of the sF adduct,
leading to SNAr reaction, was a competing process. This is
the first proof that also in the gas phase formation of sH
adduct proceeds faster than sX adduct and only when X=
Scheme 1. Relation of rates of nucleophilic addition at the position occupied
F, rates of these two processes are comparable. The exper-
imental results are in full agreement with quantum chemi-
cal calculations.
by halogen and hydrogen.
phase. As demonstrated by our group[5] and other research-
ers,[6] strongly electrophilic nitroarenes can form anionic s ad-
ducts in the gas phase. In the case when sX adduct is formed,
it reacts further, finally yielding an anion of the resulting SNAr
reaction product.[5a] There are no published proofs for the for-
mation of the stable sX adducts in the gas phase. However,
much information concerning relations of the rates of forma-
tion of sH and sX adducts can be generated by density func-
tional theory (DFT) calculations. Calculations performed for
some simple models show that sX adduct can be either an in-
termediate or a transition state in the gas-phase SNAr reaction,
depending on the structures of the substituted arene and the
attacking nucleophile.[7] Formation of sH adducts was not
postulated in these calculations. However, according to recent
calculations, sH adducts of enolates are formed faster than iso-
meric sX adducts.[8]
Nucleophilic reagents can react with nitroarenes in a variety of
ways, as recently discussed.[1] The most important ways are ar-
omatic nucleophilic substitution of halogen (SNAr)[2] and nucle-
ophilic substitution of hydrogen (SNArH).[3] Both of these pro-
cesses have found wide application in organic synthesis.[2,3]
Both reactions proceed through the formation of anionic
s adduct: sX adduct in the first case and sH adduct in the
second one (Scheme 1).
In extensive experimental work, it was unambiguously
shown that the formation of sH adduct is a much faster pro-
cess compared with the formation of sX adduct.[1–3] However,
further transformation of the sH adduct requires special reac-
tion conditions and/or specific structure of the attacking nucle-
ophile, because hydride anion cannot depart spontaneously as
the leaving group. When these conditions are not fulfilled, the
formation of sH adduct is ineffective and, due to reversibility of
its formation, SNAr reaction can proceed. In the case when
both reactions are possible, their relative rates depend on the
reaction conditions and can be precisely controlled.[4]
In mass spectrometry studies, the most common way to
obtain structural information about an ion is to fragment it
and measure the masses of the resulting fragmentation ions.
Unfortunately, our extensive studies have shown that it was
not possible to distinguish between sH and sX adducts, be-
cause the former show no specific fragmentation patterns
except for the dissociation, yielding the starting nitroarene and
nucleophile. This is because the dissociation of the sH adduct
into substrates is the reaction channel with the lowest activa-
tion energy. To overcome this problem, we decided to study
the formation of sH and sX adducts in intramolecular reactions
in the gas-phase. This should significantly increase the proba-
bility of sH adduct formation due to geometrical reasons and,
consequently, give chance for fragmentation channels other
than simple reversion of the adduct formation.
To get deeper insight into the factors governing the relative
rates of the SNAr and SNArH reactions, and to avoid the effects
of the solvent and counter-ion accompanying the attacking
nucleophile, these processes should be studied in the gas
[a] K. Błaziak, Prof. M. Ma˛kosza, Prof. W. Danikiewicz
Institute of Organic Chemistry, Polish Academy of Sciences
Kasprzaka 44/52, 01-224 Warsaw (Poland)
E-mail: witold.danikiewicz@icho.edu.pl
Searching for the best model to study direct competition
between the formation of sH and sX adducts in the intramolec-
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201406542.
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ular reactions, we chose N-(2-X-5-nitro-phenyl)-N-methyl-acet-
amides (1a–c, X=H, F, Cl). The compounds 1b and 1c should,
after deprotonation, yield an appropriate carbanion that subse-
quently attacks either position 6, yielding sH adduct, or posi-
tion 2, yielding sX adduct. The unsubstituted N-(3-nitro-
phenyl)-N-methyl-acetamide 1a was selected as the reference
compound.
2-X-5-nitroanilides of malonic acid, 2a–c, as the carbanion pre-
cursors. Under (À)ESI conditions, these compounds yield the
respective carboxylate anions, which, after decarboxylation in
the medium-pressure region of the ESI ion source, should give
the expected carbanions (Scheme 3). This method has been ex-
tensively explored in our lab.[5,10]
(À)ESI spectra of carboxylates 2a–c (see Figure S4–S6 in the
Supporting Information) show that the decarboxylation reac-
tion takes place even during standard conditions of ESI meas-
urements. After selection of the [MÀCO2]À ions, resulting from
compounds 2a–c with the first quadrupole of the triple quad-
rupole mass spectrometer, they were fragmented in a collision
cell and the resulting fragment ions were recorded yielding
spectra shown in Figure 1. The results can be rationalized by
the reactions shown in Scheme 3.
The reaction of compounds 1a
and 1c with a strong base has al-
ready been studied in solution.[9] It
was found that in the case of chloro
derivative 1c, the only observable re-
action is the oxidative nucleophilic
substitution of hydrogen (ONSH) and
no SNAr reaction product was detect-
ed (Scheme 2). For compound 1a, two ONSH products, in the
ortho and para positions to the nitro group, were formed.
Unfortunately, all our attempts to generate the desired car-
banions by deprotonation of compounds 1a–c in the gas
phase failed. We decided therefore to use the mono-N-methyl-
Scheme 2. Reaction of N-(2-chloro-5-nitrophenyl)-N-methyl-acetamide with
tBuOK in DMSO.
Figure 1. Fragmentation spectra acquired at CE=10 eV of [MÀCO2]À ions ob-
tained from compounds: 2a (m/z 193), 2b (m/z 211), 2c (m/z 227).
Scheme 3. Reactions of the anions of compounds 1a–c in the gas phase.
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Two fragmentation reactions are common for all three
anions 1a–c: an elimination of ketene and water molecules.
The first fragmentation is a simple heterolytic CÀN bond cleav-
age and will not be discussed here. Much more interesting is
elimination of water molecule. The proposed mechanism for
this process is shown in Scheme 3. Anions 1a–c cyclize to yield
bicyclic sH adducts 4a–c, which undergo a proton shift fol-
lowed by elimination of water molecule, yielding nitroso com-
pounds 6a–c (in anionic form). Such transformation of the sH
adduct to a nitroso compound (or its further transformation
products) is well known in solution chemistry,[3a,b,11] but has
been observed in the gas phase for the first time. Therefore,
the observation of an elimination of water from anions 1a–
c provides strong evidence that at least a fraction of these ions
can exist as sH adducts 4a–c.
In the case of fluoro derivative 1b, in addition to the reac-
tions mentioned above, elimination of HF is also observed, in-
dicating that a SNAr reaction takes place (Scheme 3). In con-
trast to the reaction taking place in solution, the anionic reac-
tion product in the gas phase is not a fluoride anion but an
anion of the organic product 8b. This is because the fluoride
anion is a very strong base in the gas phase (proton affinity
(PA)=372 kcalmolÀ1), much stronger than anion 8b (PA =
326 kcalmolÀ1). This was also proven, both experimentally and
computationally, for very similar compounds.[5a]
and F are comparable, even though the fluoride ion is known
to be the best leaving group in SNAr reactions.
In an attempt to rationalize the results described above, DFT
calculations using Gaussian 09 suite of programs[12] at
PBE1PBE/6-311+G(2d,p)//PBE1PBE/6-31+G(d) level of theory
(see Section S2 in the Supporting Information for the rationali-
zation of the selection of computational method) have been
performed to establish energy profiles of the processes of for-
mation of sX adducts, leading to the SNAr reaction products
and sH adducts, followed by the elimination of water molecule.
The results are shown in Figure 2. The results obtained show
that relative reaction rates of the SNAr and SNArH should
depend on the activation Gibbs free energy (DG°) values for
the formation of sH and sX adducts. In the case of chlorine de-
rivative 1c, DG° value for the formation of sX adduct is about
4 kcalmolÀ1 higher compared with the formation of sH adduct.
Such energy difference indicate that the SNAr reaction should
be slower than the formation of sH adduct by at least two
orders of magnitude, which is in perfect agreement with ex-
perimental results. DG° values for the formation of sH and sX
adducts from the fluorine derivative 1b differ by only 0.6 kcal
molÀ1, so both processes should proceed with comparable
rates, which again is consistent with experiment. Lower relative
intensity of the [1bÀH2O]À peak, compared with [1bÀHF]À,
can be easily explained, taking into account that the formation
of these ions require passing the second activation energy bar-
rier, which is quite significant for the former and negligible for
the latter reaction (31.7 versus 0.5 kcalmolÀ1, see Figure 2).
These preliminary results showed that our approach to
study competition between gas-phase SNAr and SNArH reac-
tions in the intramolecular mode proved to be very fruitful.
The results described above show unequivocally that in the
case of the chlorine derivative 1c, the formation of sH adduct
is at least two orders of magnitude faster than the formation
of sCl adduct, because no SNAr reaction product is observed.
However, as was shown earlier,[3b,c,4] the rates of addition of
carbanions to nitroaromatic rings in positions occupied by H
Figure 2. Calculated Gibbs free energy values and energy profiles for the SNAr and SNArH reactions of anions 1a (X=H; solid line), 1b (X=F; dotted line), and
1c (X=Cl; dashed line). PBE1PBE/6-311+G(2d,p)//PBE1PBE/6-31+G(d) method; results in kcalmolÀ1 at 298 K.
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van der Plas, Nucleophilic Aromatic Substitution of Hydrogen, Academic
Press, San Diego, 1994.
[4] M. Ma˛kosza, T. Lemek, A. Kwast, F. Terrier, J. Org. Chem. 2002, 67, 394–
400.
The experiments and calculations necessary to get the full pic-
ture of the gas-phase reactions of the anions of mono-N-
methyl-2-X-5-nitroanilides of malonic acids 2a–c are under
progress and their results will be published upon completion.
[5] a) W. Danikiewicz, T. Bienkowski, D. Kozlowska, M. Zimnicka, J. Am. Soc.
´
Mass Spectrom. 2007, 18, 1351–1363; b) T. Bienkowski, W. Danikiewicz,
Rapid Commun. Mass Spectrom. 2003, 17, 697–705; c) W. Danikiewicz, T.
Bienkowski, D. Poddebniak, J. Am. Soc. Mass Spectrom. 2004, 15, 927–
933.
Conclusion
The first observation of an elimination of water molecule from
the gas-phase intramolecular sH adducts made possible to di-
rectly compare the relative rates of the SNAr and SNArH gas-
phase reactions within the same molecule. The results ob-
tained show that, similarly to the reactions taking place in
a condensed phase, the formation of sH adduct is much faster
than the formation of sX adduct when X=Cl. For X=F, these
two processes proceed with comparable rates. Experimental
observations were supported by the results of the DFT calcula-
tions. Our results support the general statement that sH
adduct is an initial, reversibly formed intermediate in the reac-
tion of nitroarenes with carbanions, whereas formation of sX
adducts leading to SNAr reaction is a slower but irreversible
process.
[6] a) H. Chen, H. Chen, R. G. Cooks, J. Am. Soc. Mass Spectrom. 2004, 15,
998–1004; b) Y. Song, C. Chen, R. G. Cooks, Rapid Commun. Mass Spec-
trom. 2005, 19, 3493–3499; c) Y. Song, R. G. Cooks, Rapid Commun.
Mass Spectrom. 2006, 20, 3130–3138; d) B. Chiavarino, M. E. Crestoni, S.
Fornarini, F. Lanucara, J. Lemaire, P. Maꢁtre, Angew. Chem. Int. Ed. 2007,
46, 1995–1998; Angew. Chem. 2007, 119, 2041–2044; e) B. Chiavarino,
M. E. Crestoni, S. Fornarini, F. Lanucara, J. Lemaire, P. Maꢁtre, D. Scuderi,
Chem. Eur. J. 2009, 15, 8185–8195; f) B. Chiavarino, P. Maitre, S. Fornari-
ni, M. Crestoni, J. Am. Soc. Mass Spectrom. 2013, 24, 1603–1607; g) J.
Garver, Z. Yang, S. Kato, S. Wren, K. Vogelhuber, W. C. Lineberger, V. Bier-
baum, J. Am. Soc. Mass Spectrom. 2011, 22, 1260–1272.
[7] I. Fernꢂndez, G. Frenking, E. Uggerud, J. Org. Chem. 2010, 75, 2971–
2980.
[8] Q.-L. Xu, H. Gao, M. Yousufuddin, D. H. Ess, L. Kꢃrti, J. Am. Chem. Soc.
2013, 135, 14048–14051.
[9] M. Ma˛kosza, M. Paszewski, Synthesis 2002, 2203–2206.
´
´
[10] a) B. Wilenska, P. Swider, W. Danikiewicz, J. Mass Spectrom. 2014, 49,
1247–1253; b) M. Zimnicka, O. Sekiguchi, E. Uggerud, W. Danikiewicz,
Int. J. Mass Spectrom. 2012, 316, 76–83; c) M. Zimnicka, B. Wilenska, O.
Sekiguchi, E. Uggerud, W. Danikiewicz, J. Mass Spectrom. 2012, 47, 425–
438.
Acknowledgements
[11] a) Z. Wrꢄbel, A. Kwast, Synlett 2007, 1525–1528; b) W. Danikiewicz, M.
Makosza, J. Org. Chem. 1991, 56, 1283–1286.
This work has been financed by the National Science Centre,
Poland, Grant No. UMO-2012/05/B/ST4/01161. We express our
thanks to the Wroclaw Center for Networking and Supercom-
puting (WCSS) and Interdisciplinary Centre for Mathematical
and Computational Modeling (ICM) in Warsaw (grant no. G50-
2) for providing computer time and facilities.
[12] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R.
Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G. A. Petersson, H. Na-
katsuji, M. Caricato, X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G.
Zheng, J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Ha-
segawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven,
J. A. Montgomery Jr., J. E. Peralta, F. Ogliaro, M. J. Bearpark, J. Heyd,
E. N. Brothers, K. N. Kudin, V. N. Staroverov, R. Kobayashi, J. Normand, K.
Raghavachari, A. P. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi,
N. Rega, N. J. Millam, M. Klene, J. E. Knox, J. B. Cross, V. Bakken, C.
Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J.
Austin, R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin, K. Morokuma,
V. G. Zakrzewski, G. A. Voth, P. Salvador, J. J. Dannenberg, S. Dapprich,
A. D. Daniels, ꢅ. Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, D. J. Fox,
Gaussian 09, Gaussian, Inc., Wallingford, CT, 2009.
Keywords: aromatic nucleophilic substitution
·
density
functional calculations · mass spectrometry · substitution of
hydrogen
[1] M. Ma˛kosza, Chem. Eur. J. 2014, 20, 5536–5545.
[2] F. Terrier, Modern Nucleophilic Aromatic Substitution, Wiley-VCH, Wein-
heim, 2013.
[3] a) M. Ma˛kosza, K. Wojciechowski, Chem. Rev. 2004, 104, 2631–2666;
b) M. Ma˛kosza, Chem. Soc. Rev. 2010, 39, 2855–2868; c) M. Ma˛kosza,
Synthesis 2011, 2341–2356; d) O. N. Chupakhin, V. N. Charushin, H. C.
Received: December 18, 2014
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COMMUNICATION
What is faster? The first observation of
an elimination of water molecule from
the gas-phase intramolecular sH adducts
made it possible to directly compare
the relative rates of the SNAr and SNArH
gas-phase reactions within the same
molecule. The results obtained show
that the formation of sH adduct is much
faster than the formation of sCl adduct.
Experimental observations were sup-
ported by the results of the DFT calcula-
tions.
&
Aromatic Nucleophilic Substitution
K. Błaziak, M. Ma˛kosza, W. Danikiewicz*
&& – &&
Competition between Nucleophilic
Substitution of Halogen (SNAr) versus
Substitution of Hydrogen (SNArH)—A
Mass Spectrometry and
Computational Study
Chem. Eur. J. 2015, 21, 1 – 5
www.chemeurj.org
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ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ