Isotope effect profiles in the N-demethylation of N,N-dimethylanilines: A key to determine the pKa of nonheme Fe(III)-OH complexes

Article abstract of DOI:10.1039/c5cc00411j

N-demethylation of N,N-dimethylanilines promoted by [(N4Py)Fe^IVO]²⁺ occurs by an electron transfer-proton transfer (ET-PT) mechanism with a rate determining PT step. From the bell-shaped curve of the KDIE profile it has been estimated that the pK_a of [(N4Py)Fe^III-OH]²⁺ is 9.7.

Full text of DOI:10.1039/c5cc00411j

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Isotope effect profiles in the N-demethylation of
N,N-dimethylanilines: a key to determine the pKa
of nonheme Fe(III)–OH complexes†
Cite this: Chem. Commun., 2015,
51, 5032
Received 15th January 2015,
Accepted 16th February 2015
Alessia Barbieri, Martina De Gennaro, Stefano Di Stefano, Osvaldo Lanzalunga,*
Andrea Lapi, Marco Mazzonna, Giorgio Olivo and Barbara Ticconi
DOI: 10.1039/c5cc00411j
www.rsc.org/chemcomm
IV
2+
Q
N-demethylation of N,N-dimethylanilines promoted by [(N4Py)Fe
O]
occurs by an electron transfer–proton transfer (ET–PT) mechanism with a
rate determining PT step. From the bell-shaped curve of the KDIE profile it
has been estimated that the pKa of [(N4Py)FeIII–OH]2+ is 9.7.
Oxidative N-dealkylation of N,N-dialkylanilines promoted by high-
valent iron oxo species in heme1,2 and nonheme3 iron enzymes is
a process of great biological importance and has been the subject
of intense investigation by several research groups in the last three
decades. The interest in the N-dealkylation process has been
extended to the catalytic systems composed of synthetic heme4
and nonheme5–8 models and several mechanistic studies were
undertaken in order to investigate the possible mechanistic
dichotomy: electron transfer–proton transfer (ET–PT) vs. hydrogen
atom transfer (HAT) mechanism.
The mechanism of N-dealkylation of N,N-dialkylanilines promoted
by nonheme iron(IV)–oxo model compounds [(N4Py)FeIVQO]2+
and [(TMC)FeIVQO]2+ (TMC = 1,4,8,11-tetramethyl-1,4,8,11-
tetraazacyclotetradecane) has been analysed in detail by Nam
and coworkers.5 The application of several mechanistic criteria
based on a linear free-energy correlation, inter- and intramolecular
kinetic isotope effects and product analysis of probe substrate
oxidation1–2,4 strongly supported the occurrence of the ET–PT
Scheme 1 HAT vs. ET-PT mechanism in the N-demethylation of N,N-dialkyl-
anilines promoted by the nonheme oxoiron(IV) complex.
mechanism shown in Scheme 1 for the N-demethylation of complex, [(L)FeIII–OH]2+ (path b). After a rebound process (path d) a
N,N-dimethylanilines. In the first step (a) an electron transfer carbinolamine and the resting state of the nonheme iron(II) complex
from the N,N-dimethylaniline to the nonheme iron(IV)–oxo are formed. Finally decomposition of the carbinolamine leads to the
complex leads to the formation of the N,N-dimethylaniline main reaction products N-methylaniline and formaldehyde.
radical cation and the reduced iron–oxo complex, [(L)FeIIIQO]+.
The analysis of the kinetic deuterium isotope effect (KDIE)
The latter species then acts as a base deprotonating the radical profile has been applied as an additional tool to distinguish the
cation to give an a-aminomethyl radical and an iron(III)–hydroxo HAT and ET–PT pathway in the N-demethylation of N,N-dimethyl-
anilines,2,9 moreover when the ET–PT mechanism operates it
provides useful information about the rate determining step of
the whole process.2a,10
`
Dipartimento di Chimica, Sapienza Universita di Roma and Istituto CNR di
Metodologie Chimiche (IMC-CNR), Sezione Meccanismi di Reazione,
`
c/o Dipartimento di Chimica, Sapienza Universita di Roma, P.le A. Moro 5,
Along this line we considered it worthwhile to investigate
the KDIE profile in the N-demethylation of N,N-dimethyl-
anilines promoted by a mononuclear nonheme oxoiron(IV) complex,
namely [(N4Py)FeIVQO]2+ (N4Py = N,N-bis(2-pyridylmethyl)-N-bis(2-
piridyl)methylamine) (Fig. 1).
I-00185 Rome, Italy. E-mail: osvaldo.lanzalunga@uniroma1.it;
Fax: +39 06 49913629; Tel: +39 06 49913711
† Electronic supplementary information (ESI) available: Details of oxidation
procedures and calculations of pKa of 4-X-N,N-dimethylaniline radical cations
in CH3CN. See DOI: 10.1039/c5cc00411j
5032 | Chem. Commun., 2015, 51, 5032--5035
This journal is ©The Royal Society of Chemistry 2015

View Article Online
Communication
ChemComm
Table 2 Redox potential of 4-X-N,N-dimethylanilines, pKa values of
4-X-N,N-dimethylaniline radical cations and isotope effect profiles for the
N-demethylation of 4-X-N,N-dimethylanilines promoted by [(N4Py)FeIVQO]2+ a
Isotope effectsd
X
Potential(V) vs. SCEb pKa radical cationc (kH/kD)intra (kH/kD)inter
NO2 1.23
5.8
7.2
7.9
11.1
14.5
17.3
3.9(1)
4.2(2)
4.6(3)
4.5(3)
3.5(1)
2.3(1)
4.2(7)
4.2(2)
4.9(5)
4.4(1)
3.4(1)
2.3(1)
CN
CF3
Br
1.15
1.11
0.92
Fig. 1 [(N4Py)FeIVQO]2+
.
CH3 0.72
OCH3 0.55
The iron(IV)–oxo complex [(N4Py)FeIVQO]2+ was prepared by
oxidation of the corresponding iron(II) complex, [(N4Py)FeII(OTf)2],
with PhIO in CH3CN as reported in previous studies.11 After
50 min from the addition of 20 equiv. of 4-X-N,N-dimethylanilines
(X = OCH3, CH3, Br, CF3, CN, NO2) to the solution of
[(N4Py)FeIVQO]2+ in CH3CN at 25 1C, product analysis revealed
that 4-X-N-methylanilines and CH2O, identified as dimedone
adduct, were produced as major reaction products (Table 1).
Minor amounts of N-methylformanilides (4-X-C6H4N(CH3)CHO)
were also observed in addition to the N-demethylated products.
These products might be formed by further oxidation of the
a-hydroxylamine intermediate by the nonheme iron(IV)–oxo
complex8a or by the iron-catalyzed oxidation of N,N-dimethyl-
anilines in the presence of oxygen.12 The latter hypothesis is sup-
ported by the observation that the yields of N-methylformanilides are
significantly reduced when the oxidation of N,N-dimethylanilines has
been carried out in a degassed (freeze-thaw) reaction mixture.
Intramolecular KDIEs, (kH/kD)intra, were determined, by GC-MS
analysis, from the molar ratio of CH2O and CD2O (as dimedone
adducts) produced in the reactions of N-methyl-N-trideuterio-
methylanilines with [(N4Py)FeIVQO]2+.2c,d,4a,10
a
b
Measured by determining the CH2O/CD2O ratio (see the text). Data
c
obtained in CH3CN, see ref. 15 and 16. In CH3CN, calculated by
applying a thermochemical cycle, see ref. 10 and 15. Average of at
least three independent determinations. The error (standard deviation)
in the last significant digit is given in parentheses.
d
The intra and intermolecular KDIE values are reported in
Table 2 together with the one-electron oxidation potentials (E1)
of the N,N-dimethylanilines.
Data in Table 2 clearly show that the (kH/kD)intra values are
significantly influenced by the nature of the aryl substituents,
in particular a rise in these values followed by a decrease on going
from electron withdrawing to electron releasing substituents is
observed. This trend is different from that observed in the hydrogen
abstraction from 4-X-N,N-dimethylanilines by the tert-butoxyl radical2c
where a steady decrease of the (kH/kD)intra values was observed upon
decreasing the electron withdrawing properties of the substituents.
The observation of a maximum value in the profile is instead in
accordance with that observed in the deprotonation of 4-substituted-
N,N-dimethylaniline radical cations by pyridine, the maximum
value of (kH/kD)intra being observed for the radical cation whose
pKa is comparable with that of the proton abstracting base.2c
Thus the KDIE profile further support the occurrence of an
ET–PT mechanism in the N-demethylation of N,N-dimethylanilines
promoted by [(N4Py)FeIVQO]2+.‡
The observation that the inter- and intramolecular KDIE values
are greater than 1 implies that the first ET process is coupled with
the ensuing PT process. As previously found in the N-demethylation
catalysed by the heme model system iron tetramesitylporphyrin,2a
the observation of high KDIE values in the ET–PT mechanism was
interpreted on the basis of a competition between back electron
transfer from the reduced iron–oxo complex to the nitrogen radical
cation (i.e., kÀet in Scheme 1) and proton transfer from the nitrogen
radical cation to the reduced iron–oxo complex (i.e., the PT step in
Scheme 1). Using the steady-state assumption, the [N,N-dimethyl-
aniline radical cation/reduced iron–oxo complex] pair is constant,
it is possible to derive an expression that relates (kH/kD)inter and
(kH/kD)intra (eqn (1)).2a
Intermolecular KDIEs, (kH/kD)inter, were obtained in a similar
way using the ratio of the dimedone adducts of CH2O and CD2O
produced in competitive experiments by reacting an equimolecular
mixture of N,N-dimethylaniline and N,N-bis(trideuteriomethyl)-
aniline with [(N4Py)FeIVQO]2+.
Table 1 Products and yields in the oxidation of 4-X-N,N-dimethylanilines
by [(N4Py)FeIVQO]2+ in CH3CN at 25 1Ca
Yieldsb
X
NO2
6.9
7.7c
9.4
9.5
8.7
8.8
9.7c
6.0
1.0
—
2.2
2.5
2.1
2.7
—
CN
CF3
Br
(kH/kD)inter = (kH/kD)intra {(kD/kH)intra + (kÀet/kH)}/{1 + (kÀet/kH)}
(1)
CH3
when the ET is the rate-determining step (kÀet/kH { 1), eqn (1)
reduces to (kH/kD)inter = 1. On the other hand, when kÀet/kH c 1
it becomes (kH/kD)inter = (kH/kD)intra as observed in our case.§
Thus, our results are consistent with the currently accepted
OCH3
2.8
a
Iodosylbenzene (12.5 mmol), [(N4Py)FeII(OTf)2] (2.5 mmol) and 4-X-N,N-
b
dimethylanilines (50 mmol) in CH3CN (500 mL). Yields (mol%) refer to
the amount of substrates. In the absence of oxygen (freeze-thaw cycles). ET–PT mechanism for the N-demethylation of N,N-dimethylanilines
c
This journal is ©The Royal Society of Chemistry 2015
Chem. Commun., 2015, 51, 5032--5035 | 5033

View Article Online
ChemComm
Communication
promoted by nonheme iron complexes5–7 and suggest that
Interestingly, the pKa value (9.7) obtained for [(N4Py)FeIII–OH]2+ is
N-demethylation by [(N4Py)FeIVQO]2+ proceeds via a rate deter- in excellent agreement with that (pKa D 10) calculated for the same
mining proton transfer step. In this respect it has to be noted species by applying the thermochemical cycle defined by eqn (3).22
that an ET followed by rate-limiting deprotonation of the In eqn (3), BDEO–H is the dissociation energy of the O–H bond in
radical cations and subsequent rapid ET from the deprotonated [(N4Py)FeIII–OH]2+ (78 Æ 2 kcal molÀ1),18b E1 is the reduction
radicals has been proposed for the hydride transfer from NADH potential of [(N4Py)FeIVQO]2+ (0.75 V, the value of 0.51 V vs. SCE
analogues to [(N4Py)FeIVQO]2+ and other nonheme iron(IV)–oxo in CH3CN17 was adjusted to the NHE scale by adding 0.24 V) and
complexes.19
C is a constant that accounts for the redox potential of the couple
The analysis of the dependence of (kH/kD)intra on the pKa of the (H+/Hꢀ) and is dependent on solvent and the reference electrode
aniline radical cations provides useful information on the strength used (47.2 kcal molÀ1 for CH3CN and NHE reference electrode).15
and nature of the deprotonating base.10 The pKa values of the
1.37pKa = BDEO–H À 23.06E1 À C
(3)
N,N-dimethylaniline radical cations in CH3CN, estimated by apply-
ing a thermochemical cycle, are reported in Table 1 (the details of
calculations are provided in the ESI†).10,15 The plot of the (kH/kD)intra
values as a function of the pKa of the N,N-dimethylaniline radical
cations shows a bell-shaped profile with the (kH/kD)intra values that
increase up to a maximum value and then decrease upon increasing
the pKa (Fig. 2). The solid curve reported in Fig. 2 is obtained by
It has to be noted that direct experimental determination of pKa
values of nonheme iron(III)–hydroxo and manganese(III)–hydroxo
complexes has been reported only for those systems where the
ligand provides a sufficient stabilization of the active species.23
The analysis of the KDIE profile in the N-demethylation of
N,N-dimethylanilines promoted by nonheme iron complexes
might provide a useful tool for the determination of the pKa values
for iron(III)–hydroxo complexes characterized by low stability. It
is important to stress that the evaluation of these parameters in
association with the redox potentials of iron–oxo complexes is
of fundamental importance for the analysis of HAT processes
promoted by these reactive species.
In summary, we have shown that the application of the
kinetic isotope effect profile in the N-demethylation of
N,N-dimethylanilines promoted by the nonheme iron–oxo complex
[(N4Py)FeIVQO]2+ provided a pKa value of 9.7 for [(N4Py)FeIII–OH]2+.
Future analysis of isotope effect profiles in the N-demethylation
of N,N-dimethylanilines will be extended to other nonheme
high-valent iron–oxo and manganese–oxo complexes aimed at
determining the pKa values for the protonated form of the
reduced metal–oxo complexes.
fitting the experimental data to eqn (2) [where DpKa = pKa À pKa(max)
]
which is based on Marcus theory applied to acid-base reactions.20
log(kH/kD) = [1 À (2.3RTDpKa)2/lHlD] log(kH/kD)(max)
(2)
From the quite satisfactory fit (r2 = 0.995) it is possible to
determine the values of pKa(max) (9.7) and lHlD (44.9 kcal2 molÀ2).
By assuming that the reorganization energies associated with
proton and deuteron abstraction are equal, the l value for this
process is 6.7 kcal molÀ1. Interestingly, this value is very close
to that (6.2 kcal molÀ1) determined when the same eqn (2)
was applied to the (kH/kD)intra vs. pKa plot in the oxidation of
N,N-dimethylanilines catalysed by the water soluble iron(III)
tetrasulfonatophenylporphyrin.10
According to the theory, the maximum of the bell-shaped curve
should be reached when the pKa of the N,N-dimethylaniline radical
cation equals that of the protonated form of the abstracting base,20,21
i.e. the nonheme iron(III) hydroxo complex [(N4Py)FeIII–OH]2+.
Notes and references
‡ The ET-PT mechanism has been confirmed by the analysis of the
N-dealkylation products of the least oxidizable aniline 4-NO2-C6H4N(CH3)-
(CH2CH3) promoted by [(N4Py)FeIVQO]2+. 4-NO2-C6H4NH(CH2CH3) was
formed as the major product, as expected when an ET-PT mechanism is
operating.5,13 Accordingly, the deprotonation of the methyl group of the
radical cation is favored with respect to the proton transfer from the
ethyl group on the basis of the higher acidity of the methyl proton as
compared to the ethyl one.1g,h On the other hand, formation of
deethylated product would be preferred in HAT processes since bond
dissociation energy (BDE) for the C–H bond in the methylene group is
lower than that of the methyl C–H bond.14
§ With the exclusion of 4-CH3O-C6H4N(CH3)2, relatively high kÀet values
are expected on the basis of the endergonic ET process. Accordingly the
oxidation potentials of the N,N-dimethylanilines4a,16 (see Table 2) are
comparable (4-CH3O-C6H4N(CH3)2) or higher than the reduction potential
of [(N4Py)FeIVQO]2+ (0.51 V vs. SCE).17 Even though the latter value has to be
taken with caution in view of the complexity of the electrochemical
behaviour of the FeIV/FeIII couple in CH3CN, the more reliable and
significant higher value (0.9 V vs. Fc+/0), determined by spectropotentio-
metric studies in CH3CN in the presence of 0.1 M H2O, refers to the one-
electron reduction of [(N4Py)FeIVQO]2+ coupled with the transfer of a
proton to give [(N4Py)FeIII–OH]2+ 18
.
1 (a) A. H. Meyer, A. Dybala-Defratyka, P. J. Alaimo, I. Geronimo, A. D.
Sanchez, C. J. Cramer and M. Elsner, Dalton Trans., 2014, 43, 12175;
(b) K. M. Roberts and J. P. Jones, Chem. – Eur. J., 2010, 16, 8096;
(c) M. N. Bhakta and K. Wimalasena, Eur. J. Org. Chem., 2005, 4801;
Fig. 2 Dependence of (kH/kD)intra for the oxidative N-demethylation of
N-methyl-N-trideuteriomethylanilines promoted by [(N4Py)FeIVQO]2+ on
the pKa of 4-X-N,N-dimethylaniline radical cations in CH3CN.
5034 | Chem. Commun., 2015, 51, 5032--5035
This journal is ©The Royal Society of Chemistry 2015

View Article Online
Communication
ChemComm
(d) P. R. Ortiz de Montellano, Cytochrome P450: Structure, Mechanism,
and Biochemistry, Kluwer Academic/Plenum Publishers, New York,
J. Am. Chem. Soc., 2003, 125, 12670; (c) Y. Wang, D. Kumar, C. Yang,
K. Han and S. Shaik, J. Phys. Chem. B, 2007, 111, 7700.
3rd edn, 2005; (e) M. N. Bhakta, P. F. Hollenberg and K. Wimalasena, 10 E. Baciocchi, M. F. Gerini, O. Lanzalunga, A. Lapi, M. G. Lo Piparo
J. Am. Chem. Soc., 2005, 127, 1376; ( f ) M. N. Bhakta and K. Wimalasena, and S. Mancinelli, Eur. J. Org. Chem., 2001, 2305.
J. Am. Chem. Soc., 2002, 124, 1844; (g) C. L. Shaffer, S. Harriman, 11 J. Kaizer, E. J. Klinker, N. Y. Oh, J.-U. Rohde, W. J. Song, A. Stubna,
Y. M. Koen and R. P. Hanzlik, J. Am. Chem. Soc., 2002, 124, 8268;
(h) C. L. Shaffer, M. D. Morton and R. P Hanzlik, J. Am. Chem. Soc., 2001,
123, 8502; (i) O. Okazaki and F. P. Guengerich, J. Biol. Chem., 1993,
J. Kim, E. Mu¨nck, W. Nam and L. Que, Jr., J. Am. Chem. Soc., 2004,
126, 472; M. Lubben, A. Meetsma, E. C. Wilkinson, B. Feringa and
L. Que, Jr., Angew. Chem., Int. Ed., 1995, 34, 1512.
268, 1546; ( j) F. P. Guengerich, C.-H. Yun and T. L. Macdonald, J. Biol. 12 D. Narog, U. Lechowicz, T. Pietryga and A. Sobkowiak, J. Mol. Catal. A:
Chem., 1996, 271, 27321; (k) F. P. Guengerich and T. L. Macdonald, Acc. Chem., 2004, 212, 25.
Chem. Res., 1984, 17, 9; (l) T. L. Macdonald, W. G. Gutheim, R. B. Martin 13 E. Baciocchi, M. Bietti, O. Lanzalunga, A. Lapi and D. Raponi,
and F. P. Guengerich, Biochemistry, 1989, 28, 2071. J. Org. Chem., 2010, 75, 1378.
2 (a) Y. Goto, Y. Watanabe, S. Fukuzumi, J. P. Jones and J. P. Dinnocenzo, 14 D. Griller, J. A. Howard, P. R. Marriott and J. C. Scaiano, J. Am.
J. Am. Chem. Soc., 1998, 120, 10762; (b) J. I. Manchester, J. P. Dinnocenzo, Chem. Soc., 1981, 103, 619.
L. Higgins and J. P. Jones, J. Am. Chem. Soc., 1997, 119, 5069; 15 V. D. Parker and M. Tilset, J. Am. Chem. Soc., 1991, 113, 8778.
(c) S. B. Karki, J. P. Dinnocenzo, J. P. Jones and K. R. Korzekwa, J. Am. 16 P. Luo, A. M. Feinberg, G. Guirado, S. Farid and J. P. Dinnocenzo,
Chem. Soc., 1995, 117, 3657; (d) J. P. Dinnocenzo, S. B. Karki and
J. P. Jones, J. Am. Chem. Soc., 1993, 115, 7111.
3 Y. Mishina and C. He, J. Inorg. Biochem., 2006, 100, 670; Y. Mishina and
J. Org. Chem., 2014, 79, 9297–9304; G. W. Dombrowski,
J. P. Dinnocenzo, P. A. Zielinski, S. Farid, Z. M. Wosinska and
I. R. Gould, J. Org. Chem., 2005, 70, 3791–3800.
C. He, J. Am. Chem. Soc., 2003, 125, 8730; S. C. Trewick, T. F. Henshaw, 17 Y.-M. Lee, H. Kotani, W. Nam and S. Fukuzumi, J. Am. Chem. Soc.,
R. P. Hausinger, T. Lindahl and B. Sedgwick, Nature, 2002, 419, 174;
P. O. Falnes, R. F. Johansen and E. Seeberg, Nature, 2002, 419, 178.
4 (a) E. Baciocchi, O. Lanzalunga, A. Lapi and L. Manduchi, J. Am.
Chem. Soc., 1998, 120, 5783; (b) Y. Urano, T. Higuchi, M. Hirobe and
T. Nagano, J. Am. Chem. Soc., 1997, 119, 12008; (c) J. R. Lindsay
Smith and D. N. Mortimer, J. Chem. Soc., Perkin Trans. 2, 1986, 1743l;
(d) T. Groves and T. E. Nemo, J. Am. Chem. Soc., 1983, 105, 6243.
5 K. Nehru, M. S. Seo, J. Kim and W. Nam, Inorg. Chem., 2007, 46, 293.
2008, 130, 434.
18 (a) D. Wang, K. Ray, M. J. Collins, E. R. Farquhar, J. R. Frisch,
´
L. Gomez, T. A. Jackson, M. Kerscher, A. Waleska, P. Comba,
M. Costas and L. Que, Jr., Chem. Sci., 2013, 4, 282; (b) D. Wang,
M. Zhang, P. Bu¨hlmann and L. Que, Jr., J. Am. Chem. Soc., 2010,
132, 7638.
19 S. Fukuzumi, H. Kotani, Y.-M. Lee and W. Nam, J. Am. Chem. Soc.,
2008, 130, 15134.
6 W. Nam, Y.-M. Lee and S. Fukuzumi, Acc. Chem. Res., 2014, 47, 1146. 20 R. A. More O’Ferral, in Proton-Transfer Reactions, ed. E. F. Caldin and
7 J. Park, Y. Morimoto, Y.-M. Lee, W. Nam and S. Fukuzumi, Inorg.
Chem., 2011, 50, 11612.
8 (a) D. D Do Pham, G. F. Kelso, Y. Yang and M. T. W. Hearn, Green
V. Gold, Chapman and Hall, London, 1975, ch. 8.
21 L. Melander and W. H. Saunders, Jr., Reaction Rates of Isotopic
Molecules, Wiley, New York, 1980, ch. 5.
Chem., 2014, 16, 1399; (b) S. Yoon and S. J. Lippard, Inorg. Chem., 22 (a) J. M. Mayer, Acc. Chem. Res., 1998, 31, 441; (b) F. G. Bordwell,
2006, 45, 5438; (c) D. Lee and S. J. Lippard, J. Am. Chem. Soc., 2001,
123, 4611.
9 (a) C. Li, W. Wu, K.-B. Cho and S. Shaik, Chem. – Eur. J., 2009,
J.-P. Cheng, G.-Z. Ji, A. V. Satish and X. Zhang, J. Am. Chem. Soc.,
1991, 113, 9790; (c) V. D. Parker, K. L. Handoo, F. Roness and
M. Tilset, J. Am. Chem. Soc., 1991, 113, 7493.
15, 8492; (b) J. Shearer, C. X. Zhang, L. Q. Hatcher and K. D. Karlin, 23 R. Gupta and A. S. Borovik, J. Am. Chem. Soc., 2003, 125, 13234.
This journal is ©The Royal Society of Chemistry 2015
Chem. Commun., 2015, 51, 5032--5035 | 5035