Competition of Nucleophilic Aromatic Substitution, σ-Bond Metathesis, and syn Hydrometalation in Titanium(III)-Catalyzed Hydrodefluorination of Arenes

Article abstract of DOI:10.1002/asia.201601036

Several functionalized and non-functionalized perfluoroarenes were catalytically transformed into their para-hydrodefluorinated products by using catalytic amounts of titanocene difluoride and stoichiometric amounts diphenylsilane. Turnover numbers of up to 93 were observed. Solution density functional theory calculations at the M06-2X/TZ(PCM)//M06-2X/TZ(PCM) level of theory provided insight into the mechanism of Ti^III-catalyzed aromatic hydrodefluorination. Two different substrate approaches, with a Ti–F interaction (pathway A) and without a Ti–F interaction (pathway B), are possible. Pathway A leads to a σ-bond metathesis transition state, whereas pathway B proceeds by means of a two-step mechanism through a syn-hydrometalation intermediate or through a Meisenheimer intermediate. Both pathways are competitive over a broad range of substrates.

Full text of DOI:10.1002/asia.201601036

CHEMISTRY
AN ASIAN JOURNAL
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Accepted Article
Title: Competition of SNAr, SBM and syn hydrometallation in titanium (III) catalyzed
HDF of arenes
Authors: Dieter Lentz; Juliane Kru¨ger; Jakob Leppkes; Christian Ehm
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Competition of SNAr, SBM and syn hydrometallation in titanium
(III) catalyzed HDF of arenes
Juliane Krüger,[a] Jakob Leppkes,[a] Christian Ehm*[b] and Dieter Lentz*[a]
Abstract:
Several
functionalized
and
non-functionalized
the trimeric metal fluoride species (Cp2TiF)3 (4-trimer) because
catalyst regeneration using silanes is endergonic.[8] Recently,
the method was used as a synthetic tool to synthesize
functionalized aromatic compounds inaccessible by conventional
routes in high regioselectivity.[9]
perfluoroarenes are catalytically transformed into their para
hydrodefluorinated (HDF) products by using catalytic amounts
titanocene difluoride and stoichiometric amounts diphenylsilane.
Turnover numbers (TON) up to 93 are observed. Solution DFT
calculations at the M06-2X/TZ(PCM)//M06-2X/TZ(PCM) level of
theory provide insight into the mechanism of Ti(III)-catalyzed
aromatic HDF. Two different substrate approaches, with Ti-F
interaction (pathway A) and without Ti-F interaction (pathway B), are
possible. Pathway A leads to SBM TS, whereas pathway B proceeds
via
a
two-step mechanism through
a syn hydrometallation
intermediate or through
a
Meisenheimer intermediate. Both
pathways are competitive over a broad range of substrates.
Introduction
Scheme 1. Catalytic cycle for Ti-catalyzed HDF of fluorinated olefins (E/Z-
isomers (3a/b)).
In the fields of pharmaceutical and agricultural chemistry as well
as in the area of material science organo fluorine compounds
receive increasing attention because of their unique properties.[1]
Two routes can lead to the synthesis of fluorinated building
blocks: either selective fluorination at desired positions in the
molecule via C-H or C-X bond activation,[2] or selective
defluorination via C-F bond activation, starting from per- or
Theoretical studies on group 4 d1-metallocene-catalyzed HDF
are unavailable but some theoretical studies on C-F bond
activation reactions of archetypical C6F6 and C6F5H with group 4
d0 metal hydride systems have been published. Two distinct
mechanisms have been discussed: nucleophilic aromatic
substitution (SNAr) and σ-bond metathesis (SBM).[10] DFT
calculations for group 3 metal hydrides revealed a multistep
‘harpoon’ mechanism.[11]
In the following, we will give experimental and computational
results for HDF reactions of 1 with a variety of perfluorinated
arenes and rationalize the observed regioselectivity and activity
trends as well as the underlying mechanisms.
polyfluorinated moieties.[3] C-F bond activation poses
a
significant chemical challenge;[4] the current state of the art has
been extensively reviewed.[3l–o],[3i,5] Hydrodefluorination (HDF) of
fluorinated olefins and arenes can be achieved using transition
metal hydrido complexes,[5e,6] often catalytically. However, most
systems
rely
on
expensive
late
transition
metal
compounds.[6f,l,m,q,r,7] Some group 4 catalyzed processes are
known.[6e,q] In 2010, we reported the first Ti-catalyzed HDF of
fluoroalkenes,[6i] employing a commercially available and air-
stable precatalyst (titanocene difluoride, 1a) and an inexpensive
hydride source (diphenylsilane, 2). Extended studies indicate a
titanium (III) hydrido complex (1) as the active species, which
forms a titanium (III) fluoride (4) via F/H exchange with
fluorinated olefins (3). Resting state of this catalytic process is
Results and Discussion
We have shown,[6p] that various fluorinated olefins can be
conveniently defluorinated using 1a and 2. To explore scope and
limitations of this catalytic system for aromatic HDF we tested
various functionalized and non-functionalized perfluorinated
arenes (Table 1). Para-HDF of pentafluoropyridine (5) and
perfluorotoluene (6) to 5a and 6a proceeds smoothly at room
temperature with 1.2 mol % catalyst loading (entries 1 and 5).
Under forcing conditions, 2nd HDF in ortho position occurs for 5
(entry 3). If toluene (non-coordinating) is used as reaction
medium only the ortho HDF product 5c is formed in traces (entry
4). For perfluorobiphenyl (7), -naphthalene (8) and -benzene (9)
longer reaction times, increased amount of 1a and for 9 also a
higher reaction temperature is required for high conversions
(entries 7, 8, 11). For those three substrates mixtures of 1st and
2nd HDF products are obtained, for 7 2nd HDF occurs in para
[a]
[b]
J. Krüger, J. Leppkes, Prof. Dr. D. Lentz
Freie Universität Berlin
Institut für Chemie und Biochemie, Anorganische Chemie,
Fabeckstr. 34-36, 14195 Berlin (Germany)
E-mail: dieter.lentz@fu-berlin.de
Dr. C. Ehm
Università di Napoli Federico II
Dipartimento di Scienze Chimiche
Via Cintia, 80126 Napoli (Italy)
Supporting information for this article is given via a link at the end of
the document.
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position and for 8 and 9 in para and ortho position. In 7 both
HDF of which several can be ruled out based on computational
and experimental results.
‘quasi-identical’
para
positions
are
activated.
The
hydrodebrominated product is formed when 10 is used (entry
12); similar results were reported for the Zr-catalyzed HDF.[6q]
Interestingly, the hydrodebromination is catalytic although only
low TON are observed; furthermore, there are no 2nd HDF
products as observed for 9, indicating that the catalytic active
species 1 is poisoned. Only stoichiometric HDF is observed for
substrates with electron donating groups 11 and 12 leading to
Possible mechanisms. Two different reaction pathways (SBM
and SNAr) have been proposed in the literature for HDF of
perfluoroarenes using group 4 transition metals (d0 systems).
The key differences between both mechanisms are:

The existence of an intermediate (Meisenheimer-type
complex) in SNAr while SBM proceeds without
formation of an intermediate.
the para HDF products, respectively (entries 13, 15).
A


Attack of a nucleophile in SNAr vs. attack of a
(polarized) bond in SBM.
competing hydrosilylation (or hydrometallation) reaction of 11 as
described by Buchwald for reactions of imines with 1a or (S,S)-
(EBTHI)TiF2 and PhSiH3 can be ruled-out by 19F-NMR
spectroscopy.[12] Since the catalyst is very Lewis-acidic, it
appears plausible that it is captured by the donor function in 11
and 12 and thus nearly inactive. Adduct formation of titanocene
(III) derivatives with various organic cyanides was also reported
by Teuben.[13] To test this assumption, we added equimolar
amounts of 11 to a catalytic run of 5 (entry 12) under similar
reaction conditions (cf. entry 2). In contrast to the fast
consumption of 5 (1 h, 78 % conversion) only traces of para-
HDF product could be detected even after prolonged reaction
times.
Selectivity and activity in SNAr reactions,[14,16] is based
on electronic features of the substrate (preferred point
of attack of a nucleophile/partial charge at the carbon
atom). Selectivity/activity in SBM is usually discussed
as a result of differences in bond strengths due to
considerable bond elongation in the TS.[17]
Additionally, concerted SNAr (cSNAr), multistep ‘harpoon’
mechanism via intermediate formation of HF (rare earth
metallocenes) and single electron transfer (SET, proposed for
late transition metal systems) have been shown to be possible
mechanisms in HDF reactions.[11,18]
The active species. Cp2Ti-H (1) is a Ti(III) system, with a d1
configuration. The unpaired electron (SOMO) is located in a dz
2
type orbital that points towards incoming substrates as shown in
Figure 1 on the example of substrate 9. This leads to severe
substrate-catalyst interference and endergonic formation
energies of metal-fluoro arene adducts, in difference to group 3
metallocene systems (d0).[11] Even strong donors like RNO2 (12)
or RCN (11) are only weakly coordinated.
Scheme 2. Experimentally observed reactivity and selectivity trends for
aromatic HDF using catalyst 1 in polar solvents.
Interestingly, even for an electron donating substituent like CH3
para-HDF is observed, likely due to the influence of multiple
fluorine substituents outweighing just one R-group (entry 16).[14]
However, the reaction proceeds slower and needs high
temperatures and higher amounts of catalyst to arrive at 100 %
conversion (80 % yield of the para-HDF product, 20 % not
identified side product). The observed selectivities match those
of classical SNAr reactions, for example 5-7, 11, 12 and 13 react
at the 4-position and 7a at 4’-position respectively (Scheme 2).
Mechanistic Studies on the HDF of perfluoroarenes
Figure 1. Adduct formation as kinetic trap. Gibbs free energy with respect to
isolated reactants (left), 353 K, THF. Interference of the SOMO of 1 and the
incoming substrate in adduct 1-9(η1) (right).
‘Harpoon’ and SET mechanism can be ruled out experimentally
and computationally. The lack of an open coordination site in 1
and substrate-SOMO interference will raise the barrier for the
‘harpoon’ mechanism significantly. In fact, we were not able to
locate a ‘harpoon’ pathway for any of the substrates. The
‘harpoon’ mechanism was shown to yield subsequent activity
after the first C-F activation via activation of the newly formed C-
DFT calculations using Gaussian09,[15] at the M06-
2X/TZ(PCM)//M06-2X/TZ(PCM) level of theory have been
employed to gain a deeper understanding for the underlying
mechanism and to understand experimentally observed
reactivity and selectivity trends for substrates 5, 6, 9, 11, 12 and
13 (see Scheme 2 for structures). We will first discuss
particularities of the active species and possible mechanisms for
H
bond and intermediate aryne formation for which no
experimental indication was observed. SET-mechanism
A
requires transfer of the unpaired electron to the substrate but
can be excluded applying Marcus theory: SET from 1 to 9 is
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highly endergonic and the associated barrier is very high (>64
kcal/mol,
details
in
SI).[19]
Table 1. Catalytic HDF of perfluoroarenes with titanocene difluoride (1a, catalyst precursor) and diphenylsilane (2, hydride source) in diglyme.
1a
2
t
[h]
T
[°C]
Conv.[a]
[%]
Entry
1
Substrate
Product(s)
TON[b]
[mol %] eq.
1.2
1.4
4
rt
61
51
R1 = H, R2 = F (5a, 61 %)
(5)
2
3
R1 = H, R2 = F (78 %)
0.8
1.6
0.7
9.0
1
1
80
78
88
93
80
R1 = H, R2 = F (70 %)
100
R1 = H, R2 = H (18 %)
R1 = H, R2 = H (traces)
4[c]
0.9
1.2
0.5
0.8
96
15
110
rt
3
3
R1 = F, R2 = H (5c, 3 %)
5[d]
(6)
(7)
100
83
6[d]
0.9
1.2
1.1
1.1
24
67
rt
rt
17
19
R1 = F (17 %)
R1 = F (17 %)
7[d]
100
153
R1 = H (83 %)
8[d]
(8)
2.3
4.0
3.3
1.3
1.0
1.0
24
20
20
rt
90
0
41
-
R1, R2 = F (62 %)
R1 = H; R2 = F (23 %)
R1 = F; R2 = H (5 %)
9
-
rt
10
100
40
12
R1, R2 = F (34 %)
(9)
R1 = H, R2 = F (5 %)
R1 = F, R2 = H (1 %)
R1, R2 = F (37 %)
11
12
R1 = H, R2 = F (39 %)
R1 = F, R2 = H (17 %)
7.1
9.2
3.7
3.5
72
72
100
100
93
40
21
4
(10)
(11)
13
4.9
1.1
5.2
1.2
1.0
1.1
72
72
72
100
80
8
2
14[e]
15
5 + 11
traces 5a
traces
traces
<1
<1
(12)
(13)
100
16[d,f]
15
5.0
96
110
100
6
[a] Yields were determined by integration of 19F NMR resonances in the product mixture (versus internal fluorobenzene). If not indicated otherwise the
yields of the HDF-products are represented by the conversion. [b] The TON is calculated from the conversion of the substrate. For 2nd HDF products the
conversion is doubly considered. [c] These experiments were carried out in toluene and [d] THF. [e] An equimolar amount of 5 and 11 was used. [f] from
Ref.(59).
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Furthermore, SET was shown to be highly para selective for
C6F5H but we observe para/ortho ratios of 5:1 to 2:1 (Table 1,
entry 10 and 11)
elimination has a lower barrier. Pathway A is slightly preferred
over B (-1.5 kcal/mol). Formation of the four membered TS,
TSA9-9a and TSB9-9a, from the isolated reactants is the
selectivity determining and rate limiting step for both
mechanisms.[22]
Pathway A – TSA geometries (5, 6, 9, 11, 12, 13). Figure 4 and
Table 2 show the geometrical parameters and corresponding
free energies of the TSA. Ti shows pseudo-tetrahedral
coordination in all TS geometries, the Cp rings and the incoming
arene are oriented perpendicular to each other. All TSA are
energetically early (ΔG = 15.3 to 21.1 kcal/mol) and also
structurally rather early, meaning that the structural change in
catalyst and substrate in the TS is limited compared to the
isolated reactants.
PES profile for HDF of 9
The mechanism for HDF using 1 depends on the approach of
the reactant (Figure 2). The substrate can approach the catalyst
in-plane (pathway A) or with the π-system faced towards it
(pathway B). Pathway A allows a metal fluorine interaction,
pathway B does not. A full PES profile is shown for 9, additional
PES can be found in the SI.[20]
Figure 2. Possible substrate approaches towards the catalyst.
Reaction of 1 and 9 via pathway A leads directly to product
formation via a four-membered SBM TS (Ti-H-C-F, TSA9-9a,
+19.6 kcal/mol, Fig. 3, top). An SBM TS could not be located for
d0 metallocene systems of group
3 where a ‘Harpoon’
mechanism takes place.[11] An IRC scan shows that C-H bond
formation is completed before C-F bond fission starts (see SI).
Substrate coordination to 1, either via HCp-Farene contacts (9-
1(HF), +3.8 kcal/mol) or fluorine coordination to the metal (9-
1(η1), +2.2 kcal/mol) is endergonic. The HDF reaction is strongly
exergonic (-77.8 kcal/mol). Formation of product adducts is
endergonic, too.
Pathway B proceeds via a four membered syn hydrometallation
TS (CorthoTi-H-Cipso, TSB9-9a, +21.1 kcal/mol) through a
hydrometallation intermediate (HM9-9a, -1.7 kcal/mol, Fig. 3,
bottom). The intermediate has diene character and possesses a
very elongated Ti-C bond. Subsequent F--elimination from HM9-
9a, resulting in the intermediary formation of Cp2Ti+, a fluoride
and 9a, is facile (elim.TS9-9a, +9.8 kcal/mol). Under catalytic
conditions, i.e. a large excess of silane, the strongly nucleophilic
fluoride is likely trapped by silane and the fluoride is
subsequently transferred to the Ti-species (Scheme 3);[21]
hydride transfer from the silane would not lead to the
thermodynamic minimum, 4-trimer.[8] HM has been reported
previously for Ru-catalyzed HDF, and elimination can proceed
with or without HF formation, depending on the substrate.[5e,6j]
Figure 3. PES for HDF of 9 using catalyst 1. Pathway A (top) and B (bottom).
Gibbs free energy with respect to isolated reactants (353 K, in THF).
The ‘to-be-substituted’ fluorine and the corresponding carbon
atom deviate from ring-planarity by β = 9-12°. The C-F bond is
slightly elongated by 0.02-0.09 Å while the Ti-H bond is
substantially more elongated. TSA5-5c can ‘relax’ towards the
nitrogen side and shows a dihedral angle (γ) of 8°, thus leading
to an increased distance between HCp and FAr while the C-F-Ti-H
geometry is nearly planar for all other TSA.
Scheme 3. Proposed silane assisted F--transfer to Ti. Brackets denote solvent
cage and X = H or/and F.
We were not able to locate a zwitterionic intermediate for
substrate 9. Hydrometallation in pathway B is irreversible as F--
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Figure 4. Schematic representation of the TSA viewing along the Cpcentroid-Ti-
Cpcentroid axis with an orthogonal orientation of the arene (other substituents
are omitted for clarity). The following geometric parameter are highlighted: the
Cp-Cp torsion angle (α), the H-Ti-F-C torsion angle (γ) and the Cipso-arene
tilting angle (β).
Table 2. Selected angles and bond distances of the TSA (in Å or °, respectively). They are ordered according to decreasing distance of substrate and
catalyst (H-C + Ti-F). Gibbs free energy with respect to isolated reactants (in kcal/mol). Calculated BDE values are given in the following order: para, meta,
ortho (in kcal/mol). Detailed information in SI.
TSAx-x
α
12-12a
7
11-11a
5
5-5a
4
6-6a
10
5-5c
6
5-5b
2
9-9a
6
13-13a
11
β
10
10
9
10
11
10
10
10
γ
2
1
1
3
8
1
1
2
H-C-Ti-F
ΔG
4.10
15.3
4.07
15.6
4.06
15.4
4.00
17.2
3.90
16.9
3.89
19.7
3.89
19.6
3.86
21.1
calculated bond dissociation energies of the substrates
BDE
119.6, 119.1, 117.3
121.8,
123.1
119.4, 122.9
122.0, 121.7, 120.3
123.9
121.7
121.2
121.9, 122.0, 123.5
Experimental literature BDEs for
9
: 154.0,[23] 114.0,[24] 116.6±6,[24] and calculated literature BDE for
9
: 118.1[25]
Overall, the steric congestion of the 4-membered TS geometry
correlates perfectly with associated barrier heights. TS with
lower barriers like TSA5-5a or TSA11-11a have shorter C-F and
Ti-H bonds but longer Ti-F and C-H distances (substrate-catalyst
separation). Electron withdrawing –M-substituents lower the
relative barrier for HDF. Interestingly, the experimentally
observed para selectivity for all substrates doesn’t correlate with
calculated BDE trends (Table 2). Only for 13 the para C-F bond
is predicted to be the weakest bond (only by 0.1 kcal/mol).
Pathway B – TSB geometries (5, 6, 9, 11, 12, 13).
bent fluorine substituents are observed. All TSB are energetically
relatively early (ΔG = 13.3 - 23.0 kcal/mol) and also structurally
rather early. TSB show a bond elongation of 0.01-0.06 Å (Cipso-F)
and 0.04-0.12 Å (Ti-H) for the SNAr TS and 0.02-0.03 Å (Cipso-F)
and 0.04-0.05 Å (Ti-H) for the HM TS. Considering SNAr TS the
shorter the Cipso-H distance, the higher the barrier (ΔG).
Pathway B leads either to a hydrometallation intermediate (HM
for 6, 9, 13) or a zwitterionic (Meisenheimer-type) species (5, 11,
12) and the corresponding TS (HM and SNAr) differ significantly.
Figure 5 (left) displays a schematic view along the H-Ti axis,
illustrating the two different orientation modes of the substrates
in the TSB. A Cp-Cp tilting angle (α) of 42-44° is observed for
HM TS and 30-38° for H-addition TS (Fig. 5 and Table 3). Figure
5 (right) illustrates the view perpendicular to the Cortho-Cipso bond.
The Ti-Cortho distance is shorter in the HM TS. H-addition TS
have only one bent fluorine substituent whereas for HM TS two
Figure 5. Schematic representation of the two types of TSB; view along the H-
Ti axes (the grey bars represent Cp ligands, * = Cipso) illustrating the different
approach of the substrates (left) and view perpendicular to the Cortho-Cipso bond
(right; other aromatic substituents are omitted for clarity).
Table 3. Selected angles and bond distances of the TSB (in Å or °, respectively). They are
ordered according to increasing Cipso-H distance. Gibbs free energy referred to isolated
reactants (in kcal/mol). More detailed information in SI.
TSBx-x
5-5b
H-addition TS
38
5-5c
5-5a
11-11a
12-12a
6-6a
HM TS
42
9-9a
13-13a
α
36
37
37
37
44
43
β
11
7
7
8
7
2
2
3
Cipso-H
ΔG
1.446
21.6
1.483
19.8
1.604
14.3
1.609
15.2
1.639
13.3
1.679
19.0
1.700
21.2
1.744
23.0
Pathway B - Hydrometallation intermediates and elimination
TS. Similar to 9 formation of hydrometallated intermediates is
observed for 6 and 13 (HM6-6a, HM9-9a and HM13-13a; Figure
6). The elongated Ti-Cortho bond varies from 2.368 to 2.440 Å
which lies in a similar range as compared to the Ti-C bond
length in Cp2Ti-η2Cp (2.448(5) and 2.481(5) Å).[26] Ti-C(σ) bonds
of trivalent Cp2Ti-aryl complexes bearing a sterically demanding
R group like 2,6-Me2C6H3 or m-terphenyl are substantially
shorter with 2.178(7) and 2.242(2) Ȧ.[27,28]
Insertion of the aromatic double bond into the Ti-H bond distorts
the fluorinated aromatic system, e.g. results in a nonplanar
butadiene fragment with a dihedral angle of 41-45° and
substantially elongated Cipso-F and Cipso-H bonds (Table 4). The
C-C double bonds within the cyclohexadiene unit (1.337 to 1.353
Å) are slightly elongated and C-C single bonds (1.504 to 1.509
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Figure 8. Different zwitterionic intermediates A-C and the hydrometallation
intermediate HM (other aromatic substituents are omitted for clarity).
Å) are slightly shortened compared to classical C-C single and
double bond distances (Figure 7). Subsequently, this system
does not represent a classical Meisenheimer intermediate with
delocalized charge as described for Ru-systems.[3i,5e,6j]
Elimination from the HM intermediates is facile (+10 kcal/mol).
A-C are typical Meisenheimer complexes with delocalized
anionic charge. Interchange between these complexes is
possible via the solvent separated ion pair (SIP), if the isolated
Meisenheimer complex is stable in solution. Interestingly, for
5(para) and 5(ortho) no type B intermediate (π-bonded) is
observed but an HM intermediate. Elimination from the most
stable type A-C or HM intermediate is facile, except for 12,
where a very stable type C complex was found. This represents
Figure 6. Schematic representation of the HM intermediates and the elim.
TS for 6, 9 and 13 (* = Cipso). View perpendicular to the Cortho-Cipso bond (top)
a dead end in catalysis and explains experimental observations
(TON <1 for 12). When optimized without the cation in solution,
only 5(para)H-, 6H-, 11H- and 12H- are predicted to be stable
anions (Figure 9). [29]
and steric congestions of the organic fragment (bottom).
Figure 9. Stability of isolated Meisenheimer type anions in solution (THF, at
273 K). Gibbs free energy (in kcal/mol) for the F- elimination TS (bold) and
C(sp3)-F bond length (blue, in Å).
Figure 7. C-C bond lengths of the cyclohexadiene moiety (black: HM
intermediate and magenta elimination TS; other aromatic substituents are
omitted for clarity).
Table 5. Stability of A-C and HM intermediates. Gibbs free
energies of the intermediate/F--elimination TS with respect to
isolated reactants (in kcal/mol).
Table 4 Selected angles and bond distances of the HM intermediate and
elimination TS (with α the C-Cipso-Cortho-C torsion angle and β the
deviation from ring planarity; in Å or °, respectively). Gibbs free energy
referred to isolated reactants (in kcal/mol). More detailed information in SI.
5(para)
7.0
5(ortho)
8.2
11
5.1
-0.6/9.1
-17.6/-6.4
-
12
2.1
-3.1/8.1
-46.9/b
-
A
B
C
HM
SIP
-
-
-
-18.5/-11.0
-6.5/8.3
9.8/11.2
-18.5/-10.9
17.7a
HM
6
elim.TS
HM
9
elim.TS
HM
13
elim.TS
5.4/9.3
0.3/8.5
a) Meisenheimer anion is unstable in solution. Value given for
Cp2Ti+ 5c +F-. b) Elimination appears to be barrierless but
α
β
41
18
15
45
22
20
43
24
20
+
significantly uphill.
Cipso-H
Cipso-F
ΔG
1.094
1.412
-3.1
1.078
1.091
1.422
-1.7
1.080
1.092
1.428
1.9
1.079
The shorter the C(sp3)-F bond the more stable the anion. The
reason for the lack of stable Meisenheimer type intermediates
for 5(meta), 5(ortho), 9 and 13 might lie in the special effects of
the fluorine substituent itself. F-substitution provides an easy
decomposition pathway to an even more stable situation; a
negative charge on F is better stabilized than on C. Additionally,
HDF faces a peculiarity that other SNAr reactions do not face, as
HF formation upon nucleophilic attack of a hydride poses
another possible decomposition pathway due to the high HF
bond energy (see ‘Harpoon’ mechanism).[11]
8.6
9.8
11.6
Pathway
B – Meisenheimer type intermediates. Those
intermediates occur post the selectivity determining step for HDF
at para and ortho positions of 5 and para positions for 11 and 12.
In solution, several different types can exist (A-C; Figure 8).
Competition of pathway A and B. Both pathways are affected
very similar by electronic tuning. Barriers are lowered the more
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Chemistry - An Asian Journal
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Figure 11. Role of the SOMO. Metal based dz2 orbital and π-system cannot
interact in pathway A in contrast to pathway B.
electron deficient the aromatic π-system becomes. It appears
that both SBM and SNAr/HM barriers follow qualitatively the
trend in predicted stability of the Meisenheimer type anions.
They do not follow trends in BDE.
Comparison of experiment and theory. Experiment and theory
are in good agreement. Experimentally, only formation of 5a is
Conclusions
HDF yields products for several perfluorinated arenes and TON
up to 93, as long as donor functions do not trap the catalyst, and
usually in high regioselectivity. Irrespective of the nature of the
substituent (electron withdrawing or electron donating) the
prevailing HDF product using 1 is the para HDF product. DFT
calculations are in good agreement with experimentally
observed reactivities and selectivities. Two different reaction
pathways are competitive over a broad range of substrates but
lead to the same product selectivity. For pathway A, SBM and
for pathway B SNAr and HM are competing mechanisms. Barrier
heights for pathway A and B follow trends in the stability of
Meisenheimer anions not BDE trends of the substrates. SET
does not play a role. Unlike shown for several other transition
metal systems SBM is preferred mechanism for HDF of the
archetypical perfluorinated arene hexafluorobenzene (9).
observed in polar solvents, consistent with barrier differences for
the three pathways >2 kcal/mol (k1/k2 = eΔΔG/RT, T = 353 K), in
line with the computationally predicted barrier difference 5a/5c of
2.6 kcal/mol. DFT predicts that 5a originates from a SNAr
pathway, while 5c originates from an SBM pathway.
Experimental Section
Figure 10. Gibbs free energy (in kcal/mol) of TSA and TSB for all substrates
illustrating the competition of pathway A (blue) and B (red; 353 K, THF).
Experimental Details.
All preparations were performed using standard vacuum-line techniques
or by working in an argon-filled glove box. 1a, 2, 5-12 were purchased
from abcr and distilled from calcium hydride (2, 5, 6, 9, 10, 11, 12) or
sublimed (1a, 7, 8). Diglyme, THF and toluene were distilled from sodium
or potassium/benzophenone.
Consistent with experiment, DFT predicts the same activity
order: 5~6>9>13>11>12. Activities for 5 (only at RT) and 11 are
lower due to adduct formation.[30] 12 leads to catalyst
deactivation via formation of stable adducts after the SNAr step
(<1 TON). While activities for 11 are likely low due to adduct
formation.
Role of the SOMO. The substrate approach also plays a crucial
role with respect to reversible spin transfer throughout the
mechanism. If the substrate approaches the catalyst in plane, no
πarene-dz2metal interaction is possible (Figure 11). In stark contrast,
a π-approach allows for such a transfer. The SOMO is
predominantly concentrated on the metal for all TSA but
delocalized over metal and arene π-system for all TSB, most
intermediates and elimination TS (see SI). A notable exception
are intermediates of type A with the carbon sp3 pointing to the
metal which are geometrically similar to TSA and do not show
delocalization. The close energetic similarity between both
substrate approaches appears to indicate that delocalization of
the SOMO results only in a minor stabilization.
Reaction conditions are listed in Table 1. In a 50 mL single-necked flask
equipped with a PTFE valve, a solution of 1a and 2 was heated until its
color changed to green (1-2 min). The substrate was added, the reaction
vessel degassed and the respective conditions (Table 1) were applied.
By opening the vessel, the reaction was stopped, accompanied by a
change of color from green to yellow; fluorobenzene was added and
stirred for 5 min and the reaction mixture was put in a NMR tube
containing C6D6. Hydrodefluorination products were identified by their
characteristic NMR spectra: 2,3,5,6-tetrafluoropyridine, 2,3,4,5-
tetrafluoropyridine
and
2,3,5-trifluoropyridine;[31]
2,2’,3,3’,4,5,5’,6,6’-nonafluorobiphenyl
α,α,α,2,3,5,6-
heptafluorotoluene;[32]
and
2,2’,3,3’,5,5’,6,6’-octafluorobiphenyl;[33]
heptafluoronaphtalene,[34]
1,2,3,4,5,6,8-
1,2,4,5,6,8-hexafluoronaphtalene[32]
and
1,2,3,4,5,8-hexafluoronaphtalene;[6q]
1,2,3,4,5-pentafluorobenzene,
1,2,4,5
tetrafluoro-
and
2,3,5,6-tetrafluoronitrobenzene,[6r]
1,2,3,4-tetrafluorobenzene;[35]
2,3,5,6-
1,2,4,5-
tetrafluorobenzonitrile;[36]
tetrafluoro-3-methyltoluene.[37]
Computational details
All structures were fully optimized at the M06-2X(PCM)[38]/6-31+(2d,p)
level using Gaussian09[15] coupled to an external optimizer (PQS;
convergence settings: DMAX 0.1, TOLG 0.0003, TOLE 0.00004, TOLD
0.0018)[39] instead of the internal Gaussian optimizer, using an ultrafine
grid (Int(Grid=ultrafine)) and standard SCF convergence quality settings
(Scf=tight) for Gaussian single point calculations. The nature of each
stationary point was checked with an analytical second-derivative
calculation (no imaginary frequency for minima, exactly one imaginary
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Chemistry - An Asian Journal
10.1002/asia.201601036
FULL PAPER
frequency for transition states, corresponding to the reaction coordinate)
and the accuracy of the TS was confirmed with an IRC scan. S2 values
for all doublet species are below 0.76. Solvent influence of polar solvents
(THF, ε=4.24) was modeled explicitly, using the polarizable continuum
model (PCM) implemented in the Gaussian 09 software suite.
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Due to the previously unknown and unusual nature of the transition
states discussed here, transition states had to be located using a suitable
guess and the Berny algorithm (Opt=TS).[40] Other established methods
did not succeed (Synchronous Transit-Guided Quasi-Newton (STQN)
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the M06-2X(PCM)[42] level of theory employing triple-ζ Dunning basis sets
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[20] PES for 6 and 13 are similar to 9, and PES for 12 is similar to 11.
[21] 10 v/v% of silane are used experimentally, strongly suggesting that
silanes are part of the coordination sphere. The fluorphilicity of silane is
likely high enough to trap the fluorine. The Ti cation will initially abstract
an F- from the silane anion as the Ti-F BDE is much higher than the Ti-
H bond BDE.
[22] Under catalytic conditions, 4 is the resting state and the rate limiting
step is regeneration + HDF. Thus an approx. 5 kcal/mol regeneration
For internal use, please do not delete. Submitted_Manuscript

Chemistry - An Asian Journal
10.1002/asia.201601036
FULL PAPER
FULL PAPER
Ti-catalyzed hydrodefluorination of
arenes proceeds in para position
regardless of the specific mechanism
(SBM, SNAr or HM). SET is not
competitive.
Juliane Krüger, Jakob Leppkes,
Christian Ehm,* Dieter Lentz*
Page No. – Page No.
Competition of SNAr, SBM and syn
hydrometallation in titanium (III)
catalyzed HDF of arenes
For internal use, please do not delete. Submitted_Manuscript