Organozirconium complexes as catalysts for markovnikov-selective lntermolecular hydrothiolation of terminal alkynes: Scope and mechanism

Article abstract of DOI:10.1021/ja103979b

The efficient and selective organozirconium(IV)-mediated, intermolecular hydrothiolation of terminal alkynes by aliphatic, benzylic, and aromatic thiols using CGCZrMe2 (CGC = Me2SiCp" NCMe3, Cp" = C5Me4), Cp*ZrBn ₃ (Cp* = C5Me5, Bn = benzyl), C

Full text of DOI:10.1021/ja103979b

Published on Web 07/09/2010
Organozirconium Complexes as Catalysts for
Markovnikov-Selective Intermolecular Hydrothiolation of
Terminal Alkynes: Scope and Mechanism
Charles J. Weiss and Tobin J. Marks*
Department of Chemistry, Northwestern UniVersity, EVanston, Illinois 60208
Received May 10, 2010; E-mail: t-marks@northwestern.edu
Abstract: The efficient and selective organozirconium(IV)-mediated, intermolecular hydrothiolation of
terminal alkynes by aliphatic, benzylic, and aromatic thiols using CGCZrMe2 (CGC ) Me2SiCp′′ NCMe3,
Cp′′ ) C5Me4), Cp*ZrBn3 (Cp* ) C5Me5, Bn ) benzyl), Cp*ZrCl2NMe2, Cp*2ZrMe2, and Zr(NMe2)4
precatalysts is reported. These transformations are shown to be highly Markovnikov-selective, with
selectivities up to 99%, and typically in greater than 90% yields. The reaction has been demonstrated on
the preparative scale with 72% isolated yield and 99% Markovnikov selectivity. A mixture of anti-Markovnikov
products is occasionally observed as a result of a known, non-organometallic, radical mechanism, which
can be suppressed by addition of a radical inhibitor. Kinetic investigations show that the CGCZrMe2-mediated
reaction between 1-pentanethiol and 1-hexyne is first-order in catalyst concentration, first-order in alkyne
concentration, and also first-order in thiol at lower concentrations but transitions to zero-order at
concentrations > 0.3 M. Deuterium labeling of the alkyne yields kH/kD ) 1.3(0.1), along with evidence of
thiol-mediated protonolytic detachment of product from the Zr center. Activation parameters for CGCZrMe2-
mediated 1-pentanethiol hydrothiolation of 1-hexyne measured over the temperature range of 50-80 °C
are ∆H‡ ) +18.1(1.2) kcal/mol and ∆S‡ ) -20.9(2.5) e.u. for [alkyne] and [thiol] at 0.2 M. These and
other findings are consistent with turnover-limiting alkyne insertion into the Zr-SR bond, followed by a
thiol-induced Zr-C protonolysis. Observed zirconium-thiolate dimers in the reaction medium suggest
instances of dimeric catalyst resting states and possible aggregated, hydrothiolation-active species.
processes.2a,5 Radical hydrothiolation yields unselective mixtures
Introduction
of E and Z vinyl sulfides (eq 1a) while organometallic catalysts
Sulfur is a significant component in many natural products,1
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for efficient and selective means of incorporating sulfur into
organic frameworks. Hydrothiolation is an atom-economical
method for the formation of C-S bonds and can be achieved
via a variety of pathways including radical4 and catalytic
offer access to Markovnikov vinyl sulfides or E anti-Markovni-
kov vinyl sulfides (eq 1b) with varying degrees of turnover and
selectivity.2a,5,6 Note that while diverse variants of organome-
tallic complex-mediated hydroelementation7 have been exten-
sively explored, including hydroamination,8 hydrophosphina-
tion,9 and hydroalkoxylation,10 only recently has hydrothiola-
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10.1021/ja103979b  2010 American Chemical Society
J. AM. CHEM. SOC. 2010, 132, 10533–10546 10533

A R T I C L E S
Weiss and Marks
employed organo-Th(IV) and organo-U(IV) complexes.11 While
some late transition metal catalysts exhibit high activity,
achieving high Markovnikov selectivity still presents a chal-
lenge, with the exception of Pd, as does competing isomerization
of the alkene product,13a double-thiolation products,5j and
product insertion into a second alkyne.5j,15 Furthermore, while
some late transition metal complexes effect efficient alkyne
hydrothiolation with benzyl and aryl thiols, few mediate
hydrothiolation with the less reactive aliphatic thiols.5c,d,i,m
Actinide complexes have demonstrated impressive hydrothi-
olation selectivity and the ability to utilize aliphatic thiols (e.g.,
eq 2);11 however the non-negligible radioactivity may render
them undesirable for large-scale use. Previous work with
rhodium catalysts demonstrated the ability to utilize both
terminal and internal alkynes with selectivity typically favoring
the linear (E) anti-Markovnikov products (e.g., eq 3)5c with the
exception of Tp*Rh(PPh3)2 where Markovnikov vinyl sulfides
are selectivey produced.5m Studies on group 10 metals find that
nickel (e.g., eq 4)5l and palladium (e.g., eq 5)5i catalysts favor
the Markovnikov product.
tion2a,5,8,11 been investigated in detail due to the historic
reputation of sulfur as a catalyst poison,5o,12 reflecting its high
affinity for ‘soft’ transition metal centers.13
Interest in homogeneous, catalytic alkyne hydrothiolation over
the past few years has yielded a number of metal complexes
competent to effect this transformation using late transition
metal2a,5,8b,14 and actinide11 catalysts. Late transition metal
catalysts include Rh,2a,5c,e,m,6,8b,14a Ir,8b Ni,5b,g,h,j-l,n Pd,5b,g,i,14
Pt,5g and Au5a complexes while actinide investigations have
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Available mechanistic data for late transition metal- and
organoactinide-mediated hydrothiolation complexes are consis-
tent with pathways in which the alkyne undergoes insertion into
either a metal-hydride or metal-thiolate bond.5c,h,j,11,14a The
accepted hydride pathway for most Rh complexes5c,14a is
initiated by π-coordination/activation of the acetylene to/by the
metal-hydride complex (Scheme 1A, step i), followed by
alkyne insertion into the Rh-H bond (Scheme 1A, step ii).
Finally, regeneration of the catalyst occurs through reductive
elimination of product followed by RS-H oxidative addition
to the metal center (Scheme 1A, step iii). Rhodium complexes
selectively yield E anti-Markovnikov products as a result of
the hydride insertion regiochemistry. In contrast, Pd,5h,14a Ni,5h,j
and Th11 complexes are proposed to effect hydrothiolation via
acetylene insertion into the metal-thiolate bond (Scheme 1B,
step i) followed by thiol-mediated displacement of product from
the metal center (Scheme 1B, step ii), resulting in Markovnikov
selectivity.
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The recently communicated activity of organoactinides for
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with what activity and selectivity, zirconium(IV) complexes
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(15) After the insertion of alkyne into the Pd-SR bond (Scheme 1B, step
i), the insertion of a second alkyne into the Pd-vinyl bond occurs
instead of the release of product from the metal center (Scheme 1B,
step ii) resulting in a diene sulfide.
(12) Hegedus, L. L.; McCabe, R. W. Chemical Industries Series, Vol. 17:
Catalyst Poisoning; 1984.
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Markovnikov-Selective Intermolecular Hydrothiolation
A R T I C L E S
Scheme 1. Proposed Alkyne Hydrothiolation Mechanisms for Late Transition Metal and Actinide Complexes
in the literature, while Zr[NMe2]4 (5) was purchased from Aldrich
and used as received. The methyltriphenylsilane 1H NMR internal
integration standard for kinetic studies was purchased from Strem,
sublimed under high vacuum, and stored in a glovebox until use.
NMR spectroscopic data for products 12, 14, 19, 21, 29, and 31
agree with the published literature spectra.5m,11,21
Physical and Analytical Measurements. NMR spectra were
recorded on Mercury 400 (400 MHz, 1H; 100 MHz, 13C; 61 MHz,
2H) and Avance III 500 (500 MHz, 1H; 125 MHz, 13C) NMR
spectrometers. Chemical shifts (δ) are referenced relative to internal
solvent resonances and reported relative to Me4Si. Spectra of air-
sensitive reactions and materials were taken in airtight, Teflon-
valved J. Young NMR tubes. Samples were heated in silicon oil
baths with the temperature controlled by an Ika ETS-D4 probe.
GC data were collected on an HP6890 GC-MS equipped with an
HP5972 detector and an HP-5MS (5% phenyl methyl siloxane, 30 m
× 250 µm × 0.25 µm) capillary column while high-resolution mass
spectra were collected on an Agilent 6210 LC-TOF (ESI, APPI)
and Thermo Finnegan MAT900 (EI).
Typical NMR-Scale Catalytic Reaction. In a glovebox, CGC-
ZrMe2 (1, 3.7 mg, 10 µmol) and methyltriphenylsilane (8.0 mg,
29.5 µmol) were dissolved in 0.6 mL of C6D6 and added to a J.
Young NMR tube. The tube was sealed, removed from the
glovebox, and attached to a high-vacuum line where 0.2 mL of
thiol and 0.2 mL of alkyne solutions (both 1.0 M in benzene-d6;
0.2 mmol; 20-molar excess) were syringed in under an argon flush.
The reaction mixture was then sealed, shaken well, degassed by a
single freeze-pump-thaw cycle, and placed in a preheated,
temperature-controlled oil bath covered with aluminum foil.
Kinetic Experiments. The same procedure as described above
was followed except that the sample was periodically cooled to
room temperature to collect 1H NMR spectra.22 Turnover frequency
(Nt) was determined by the method of initial rate23 where data points
were collected early in the reaction before the substrates had been
appreciably consumed (see Supporting Information). As a result,
the reaction during this period of time can be approximated as
pseudo-zero-order with respect to the substrate concentrations,
resulting in a linear trend. The resulting linear plots were fit by a
might be competent to mediate hydrothiolation. In past instances
of organozirconium-mediated alkyne hydroamination,8a,m,17a
Markovnikov selectivity similar to that of f-element catalysts
has been observed,8h,j suggesting that organozirconium com-
plexes may offer a selective, catalytic route to Markovnikov
vinyl sulfides. Herein, we report the first implementation of
organozirconium complexes for the Markovnikov-selective,
catalytic hydrothiolation of a broad variety of terminal alkynes
by aliphatic, benzylic, and aromatic thiols. This includes efficient
routes to Markovnikov vinyl sulfides with a wide range of thiols
and terminal alkynes. In addition, detailed mechanistic studies
probe the pathway by which this transformation occurs via
kinetic analysis, substituent effects, and deuterium-labeling
studies.
Experimental Section
Materials and Methods. Due to the air and moisture sensitivity
of the organozirconium complexes used in this study, all manipula-
tions were carried out in oven-dried, Schlenk-type glassware
interfaced to either a dual-manifold Schlenk line, high-vacuum line
(10-6 Torr), or in a nitrogen-filled glovebox (<1 ppm O2). Argon
(Airgas) was further purified by passing through columns of MnO
and activated 4Å Davison molecular sieves immediately before use.
Toluene for preparative scale and benzene-d6 (Cambridge Isotope
Laboratories, 99+ atom % D) for NMR reactions and kinetic
measurements were stored over Na/K alloy in Vacuo and vacuum
transferred immediately prior to use or were stored in a nitrogen-
filled glovebox until use. Diethylether for synthesis was distilled
from Na/benzophenone immediately prior to use. Thiols and alkynes
were purchased from Aldrich, VWR, GFS Chemicals, and Acros;
they were distilled and transferred across multiple beds of activated
Davison 4Å molecular sieves as solutions in benzene-d6 or neat,
followed by degassing (10-6 Torr) via freeze-pump-thaw meth-
ods. All substrates were stored under argon until use. Conjugated
alkynes and thiols were stored at -10 °C until use. Ethanethiol-d
(98 atom % D) was prepared according to literature methods,11
and D2O was purchased from Cambridge Isotope Laboratories (99.9
atom % D). The organozirconium precatalysts CGCZrMe2 (1),18
Cp*ZrBn3 (2),19 and Cp*ZrCl2NMe2 (3)20 were prepared as reported
(18) Carpenetti, D. W.; Kloppenburg, L.; Kupec, J. T.; Petersen, J. L.
Organometallics 1996, 15, 1572–1581.
(16) (a) Marek, I. New Aspects of Zirconium Containing Organic Com-
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and zirconium in organic synthesis; Wiley-VCH: Weinheim, 2002.
(c) Hey-Hawkins, E. Chem. ReV. 1994, 94, 1661–1717. (d) Poli, R.
Chem. ReV. 1991, 91, 509–551. (e) Cardin, D. J.; Lappert, M. F.;
Raston, C. L. Chemistry of Organo-Zirconium and -Hafnium Com-
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(17) (a) Majumder, S.; Odom, A. L. Organometallics 2008, 27, 1174–
1177. (b) Stubbert, B. D.; Marks, T. J. J. Am. Chem. Soc. 2007, 129,
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(19) Wolczanski, P. T.; Bercaw, J. E. Organometallics 1982, 1, 793–799.
(20) Irigoyen, A. M.; Martin, A.; Mena, M.; Palacios, F.; Yelamos, C. J.
Organomet. Chem. 1995, 494, 255–259.
(21) Fiandanese, V.; Marchese, G.; Naso, F.; Ronzini, L. Synthesis 1987,
1034–1036.
(22) To test for temperature-dependent mechanism changes, samples were
tested at constant temperature without the repeated heating/cooling
and showed results consistent with those which were repeatedly heated/
cooled. Additionally, no change in the catalyst or substrates were
observed as a result of the heating/cooling cycles.
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A R T I C L E S
Weiss and Marks
1
linear-regression analysis using R2 g 0.99 according to eq 6, and
Nt was calculated according to eq 7 where [catalyst]0 ) initial
concentration of precatalyst and t ) time in h. Kinetic experiments
in this study were performed at 0.2 M [thiol] and [alkyne] unless
otherwise indicated. Linear corrections for slight variations in initial
[thiol] and [alkyne] were applied as needed.
2-(Ethylthio)-1-hexene (8). H NMR (benzene-d6, 500 MHz,
δ): δ 5.01 (s, 1H); 4.66 (s, 1H); 2.43 (q, 7.5 Hz, 2H); 2.22 (t, 7.5
Hz, 2H); 1.55 (m, 2H); 1.24 (m, 2H); 1.06 (t, 7.5 Hz, 3H); 0.83 (t,
7.5 Hz, 3H). 13C NMR (benzne-d6, 125 MHz, δ): δ 146.8; 105.2;
38.1; 31.8; 25.6; 22.7; 14.4; 13.7. HRMS (EI) m/z calcd for C8H16S:
144.0973; found: 144.0966.
2-(2,2,2-Trifluoroethylthio)-1-hexene (10). 1H NMR (benzene-
d6, 400 MHz, δ): δ 4.90 (s, 1H); 4.75 (s, 1H); 2.69 (q, 10 Hz, 2H);
2.00 (t, 7.6 Hz, 2H); 1.34 (m, 2H); 1.40-1.30 (m, 2H); 1.17-1.07
(m, 2H); 0.78 (t, 7.2 Hz, 3H). 13C NMR (benzene-d6, 100 MHz,
δ): δ 143.5; 129.0; 110.2; 36.9; 33.8 (q, JFC ) 10 Hz); 31.0; 22.5;
14.3. HRMS (EI) m/z calcd for C8H13F3S: 198.0690; found:
198.0684.
[product] ) mt
(6)
(7)
m
Nt (h-1) )
[catalyst]0
2-(Phenylmethylthio)-1-hexene (17). 1H NMR (benzene-d6, 500
MHz, δ): δ 7.22 (d, 7.5 Hz, 2H); 7.08 (t, 8.0 Hz, 2H); 7.01 (t, 7.5,
1H); 4.98 (s, 1H); 4.73 (s, 1H), 3.69 (s, 2H); 2.19 (t, 7.5 Hz, 2H);
1.51 (m, 2H); 1.22 (m, 2H); 0.81 (t, 7.5, 3H). 13C NMR (benzene-
d6, 125 MHz, δ): δ 147.0; 137.6; 129.5; 129.0; 127.6; 106.3; 37.9;
36.8; 31.7; 22.7; 14.4. HRMS (EI) m/z calcd for C13H18S: 206.1129;
found: 206.1127.
Yield and Selectivity Measurements. In the glovebox,
Cp*ZrBn3 (2, 5.0 mg, 10 µmol) was dissolved in 0.4 mL of C6D6
and the resulting solution was transferred to a J. Young NMR tube.
The tube was then sealed, removed from the glovebox, and attached
to the high-vacuum line where 0.2 mL of thiol and 0.6 mL of alkyne
solutions (both 1.0 M in benzene-d6; 0.2 mmol; 20 molar excess
in thiol) were syringed in under an argon flush. The reaction mixture
was then sealed, shaken well, degassed by a single freeze-pump-
thaw cycle, and placed in a temperature-controlled, 120 °C oil bath
for 24.0 h. The product conversion and selectivity were determined
3-Cyclohexyl-2-(pentylthio)-1-propene (25). 1H NMR (benzene-
d6, 500 MHz, δ): δ 5.02 (s, 1H); 4.74 (s, 1H); 2.53 (t, 7.0 Hz, 2H);
2.18 (d, 7.0 Hz, 2H); 1.83-1.78 (m, 2H); 1.78-1.70 (m, 1H);
1.70-1.63 (m, 2H); 1.63-1.56 (m, 1H); 1.56-1.48 (m, 2H);
1.26-1.04 (m, 7H); 0.87-0.78 (m, 5H). 13C NMR (benzene-d6,
125 MHz, δ): δ 145.5; 106.0; 46.7; 37.3; 33.6; 31.9; 31.7; 28.6;
27.3; 27.0; 22.9; 14.5. HRMS (EI) m/z calcd for C14H26S: 226.1755;
found: 226.1748.
1
by H NMR and GC/MS.
General Procedure for Purification of Products. After carrying
out NMR-scale reactions as described above, the reaction mixture
was cooled to room temperature and the contents were eluted
through a silica gel plug with ∼10 mL of hexanes to remove the
catalyst. Product 35 was eluted with CH2Cl2. The filtrate was then
pumped under vacuum to remove the volatiles.
Preparative Scale Procedure. In the glovebox, Cp*ZrBn3 (220
mg, 0.44 mmol) was added to an oven-dried, 20 mL J. Young-
valved glass storage tube with a stir bar and dissolved in 10 mL of
toluene. The tube was then sealed and placed on a high-vacuum
line where 1-pentanethiol (1.0 mL, 8.1 mmol) and 1-hexyne (2.5
mL, 22 mmol)24 were syringed into the tube under an argon flush.
The vessel was next sealed and placed in a preheated 100 °C oil
bath for 24 h. After cooling, the vessel was opened to ambient and
the catalyst was removed by filtering through silica gel, eluting
with ∼20 mL of hexanes. The volatiles were then removed under
vacuum to yield pure 12 as a yellow oil (1.08 g, 5.8 mmol, 72%
yield) which was determined to be 99% Markovnikov pure by GC/
MS.
1
2-(Pentylthio)-3-phenyl-1-propene (27). H NMR (benzene-
d6, 500 MHz, δ): δ 7.20-7.16 (m, 2H); 7.15-7.10 (m, 2H);
7.06-7.01 (m, 1H); 4.96 (s, 1H); 4.73 (s, 1H); 3.44 (s, 2H); 2.42
(t, 7.5 Hz, 2H); 1.44-1.36 (m, 2H); 1.13-1.01 (m, 4H); 0.72 (t,
7.0 Hz, 3H). 13C NMR (benzene-d6, 125 MHz, δ): δ 146.4; 139.5;
129.7; 128.9; 127.1; 107.1; 44.5; 31.9; 31.8; 28.5; 22.9; 14.4. HRMS
(EI) m/z calcd for C14H20S: 220.1286; found: 220.1287.
1
3-(1-(Pentylthio)ethenyl)pyridine (33). H NMR (benzene-d6,
500 MHz, δ): δ 9.05 (s, 1H); 8.46 (dd, 5.0 Hz, 1H); 7.59 (dt, 8.0
Hz, 1H); 6.66 (dd, 8.0 Hz, 1H); 5.24 (s, 1H); 5.04 (s, 1H); 2.37 (t,
7.5 Hz, 2H); 1.40 (m, 2H); 1.15-1.05 (m, 4H); 0.77 (t, 7.0 Hz,
3H). 13C NMR (benzene-d6, 125 MHz, δ): δ 150.4; 149.2; 143.2;
136.1; 134.5; 123.4; 112.0; 32.5; 31.5; 28.7; 22.8; 14.4. HRMS
(APPI) m/z [M+H]+ calcd for C12H17NS: 208.1161; found:
208.1158.
1
Phenylacetylene-d (30-d). In an oven-dried, 200 mL Schlenk
flask, phenylacetylene (7.0 mL, 64 mmol) was dissolved in 60 mL
of anhydrous diethylether. The flask was cooled to 0 °C before the
2-(Pentylthio)-2-propen-1-amine (35). H NMR (benzene-d6,
500 MHz, δ): δ 5.16 (s, 1H); 4.74 (s, 1H); 3.26 (s, 2H); 2.49 (t,
7.5 Hz, 2H); 1.49 (m, 2H); 1.26-1.06 (m, 4H); 0.87-0.63 (bm,
5H). 13C NMR (benzene-d6, 125 MHz, δ): δ 149.5; 105.1; 48.8;
31.8; 31.5; 28.8; 22.9; 14.5. HRMS (ESI) m/z [M+H]+ calcd for
C8H18NS: 160.1154; found: 160.1155.
n
slow addition of 45 mL of BuLi solution (1.6 M in hexanes, 72
mmol) and stirring for 15 min at 0 °C, followed by 30 min at room
temperature. The flask was recooled to 0 °C, and D2O (2.5 mL,
125 mmol) was slowly added. The reaction was stirred overnight
at room temperature before the solvent was removed in vacuo, and
the product was distilled to afford a clear liquid in 57% yield. The
deuterium incorporation was determined to be 98% atom % D by
Results
The principal goal of this investigation is to explore the
efficacy and scope of organozirconium complexes in terminal
alkyne hydrothiolation processes and to elucidate the mechanism
by which this transformation occurs. Ancillary ligand effects
on catalyst stability and reactivity are first discussed, ac-
companied by a presentation of substrate scope, followed by
substrate steric and electronic effects on hydrothiolation activity
and selectivity. Finally, reaction kinetics and deuterium labeling
studies are presented, including rate law and activation param-
eters, and their implications regarding a proposed mechanistic
pathway are discussed.
1H NMR. H NMR (benzene-d6, 500 MHz, δ): δ 7.40 (m, 2H);
1
6.91 (m, 3H). 13C NMR (benzene-d6, 125 MHz, δ): δ 132.7; 129.1;
128.9; 123.1; 83.8 (t, 7.5 Hz); 78.0 (t, 38 Hz). 2H (benzene-d6, 61
MHz, δ): δ 2.68 (s).
Ethanethiol-d (7-d). 1H NMR (benzene-d6, 500 MHz, δ): δ 2.16
(m, 2H); 0.97 (t, 7.0 Hz, 1H). 13C NMR (benzene-d6, 125 MHz,
2
δ): δ 20.1; 19.3. H (benzene-d6, 61 MHz, δ): δ 1.07 (s).
(23) (a) Ansyln, E. V.; Dougherty, D. A. Modern Physical Organic
Chemistry; University Science Books: Sausalito, CA, 2006. (b)
Espenson, J. H. Chemical Kinetics and Reaction Mechanisms, 2nd
ed.; McGraw-Hill: New York, 1995. (c) Pilling, M. J.; Seakins, P. W.
Reaction Kinetics; Oxford University Press: New York, 1995.
(24) Because this reaction is first-order in thiol and alkyne, excess alkyne
is neccesary to drive the reaction to near completion. NMR scale
reactions of 6 + 11 f 12 mediated by complex 2 at 120 °C results in
50% conversion after 24 h with 2× excess alkyne while resulting in
95% conversion with 3× excess alkyne.
Ligand Effects on Catalyst Stability and Reactivity. With the
hydrothiolation of 1-hexyne as a model reaction, the catalytic
activity of a variety of organozirconium complexes was
1
examined by in situ H NMR spectroscopy for efficiency in
this tranformation. It is found that catalyst activity, stability,
9
10536 J. AM. CHEM. SOC. VOL. 132, NO. 30, 2010

Markovnikov-Selective Intermolecular Hydrothiolation
A R T I C L E S
Figure 1. 1H NMR (500 MHz) of reaction 6 + 16 f 17 mediated by 5 mol % Cp*ZrBn3 (2) precatalyst in benzene-d6 with 3× molar excess of 1-hexyne
(A), the completed reaction after 24.0 h in a 120 °C oil bath (B), and the isolated product (C, 17).
Table 1. Turnover Frequencies for the Catalytic
Zirconium-Mediated Hydrothiolation of 1-Hexyne (6) by
Benzylmercaptan (16) and 1-Penthanethiol (11)
Benzylmercaptan
Nt (h-1
1-Pentanethiol
Nt (h-1
Precatalyst
)
)
Figure 2. Zirconium thiolate dimers with µ-bridging thiolates resulting
from the reaction of Cp*ZrBn3 (20) with either benzylmercaptan (16) or
ethanethiol (7) to yield known cisoid benzylate (A) and transoid ethanethi-
olate (B) dimers.31
1, CGCZrMe2
2, Cp*ZrBn3
3, Cp*ZrCl2NMe2
4, Cp*2ZrMe2
5, Zr(NMe2)4
3.0
1.5
5.9a
--
0.7
1.5
--
low activity
--
g2.0b
Cp*2ZrMe2 (4), which is activated very slowly (i.e., undergoes
slow Zr-Me cleavage)28 and exhibits very low net activity. In
contrast, changing to benzylmercaptan (16) evidences a reverse
order of activity with CGCZrMe2 (1) exhibiting 2× the activity
of Cp*ZrBn3. Tetrakis(dimethylamido)zirconium(IV) (5) ex-
hibits higher initial reactivity than Cp*ZrBn3 (2) with benzylm-
ercaptan (16); however, gradual precipitation of zirconium-
containing side products renders the exact turnover frequency
undeterminable.29
a Catalyst structure changes are observed during the reaction likely as
a result of known chloride redistribution.30 b Exact turnover-frequency
(Nt) cannot be determined due to the catalyst precipitation after addition
of benzylmercaptan (16).
and selectivity are strongly dependent on the nature of the
zirconium ancillary ligation (a representative experiment is
shown in Figure 1). Thus, addition of 20× excess thiol to
tetrakis(dimethylamido)Zr(IV) (5) results in rapid precipitation
of a new complex which will be discussed in more detail below.
However, precipitation is not observed for cyclopentadienyl
catalysts 1-4 exept when [thiol] g 1.2 M. In contrast to reports
of excess thiol protonolytically cleaving the cyclopentadienyl
ligands of organoactinide and organolanthanide cyclopentadienyl
complexes with subsequent precipitation of aggregated thiolate
species,11,25 ring cleavage is not observed26 under the present
conditions (as assessed by in situ NMR spectroscopy), consistent
with more covalent Zr-Cp bonding.27
For the hydrothiolations surveyed, the measured turnover
frequencies (Table 1) are dependent upon the particular zirco-
nium ancillary ligation and thiol reagent. In the reaction between
1-hexyne (6) and 1-pentanethiol (11), Cp*ZrBn3 (2, Cp* )
C5Me5 Bn ) benzyl) is more than 2× as active as CGCZrMe2
(1, CGC ) Me2SiCp′′NCMe3, Cp′′ ) C5Me4) followed by
Nature of the Catalytic Species. To test for oligomeric species
31
such as the known dimers of the formula [Cp*Zr(SR)3]2
(Figure 2) under the present hydrothiolation conditions, a Teflon-
valved NMR tube was loaded with Cp*ZrBn3 (1) and a 20-fold
excess of both benzylmercaptan (16) and 1-hexyne (6). The
1
resulting H NMR spectrum (Figure 3A) of the known cisoid
[Cp*Zr(SBn)3]2 dimer (Figure 2A) at 23 °C is observed with
spectral parameters in good agreement with reported literature
NMR data.31 Upon heating the solution to 120 °C (Figure 3B),
the terminal benzylthiolate methylene protons at δ 5.11 and 4.82
ppm broaden and shift upfield to δ 4.96 and 4.73 ppm,
respectively, resulting in the latter resonance overlapping with
the bridging methylene resonance (Figure 3b). When the reaction
mixture is cooled to 60 °C (Figure 3C) and subsequently to 23
°C (Figure 3D), the methylene resonances sharpen, separate,
and return to their original frequencies. Exchange between
(25) (a) Cotton, S. Lanthanide and Actinide Chemistry; John Wiley & Sons,
Ltd: Uppingham, Rutland, U.K., 2006. (b) Li, H. X.; Ren, Z. G.;
Zhang, Y.; Zhang, W. H.; Lang, J. P.; Shen, Q. J. Am. Chem. Soc.
2005, 127, 1122–1123. (c) Aspinall, H. C., Chemistry of the f-Block
Elements; Taylor & Francis: Washington, DC, 2001. (d) Aspinall,
H. C.; Cunningham, S. A.; Maestro, P.; Macaudiere, P. Inorg. Chem.
1998, 37, 5396–5398. (e) Marks, T. J. Science, 1982, 217, 989-997.
(26) Even at [thiol] > 1.2 M, when small amounts of precipitate are formed,
no free CGCH2 ligand is observed by NMR spectroscopy.
(27) Strittmatter, R. J.; Bursten, B. E. J. Am. Chem. Soc. 1991, 113, 552–
559.
(28) Activation in 120 °C occurs slowly and thus sometimes requires placing
the reaction in a 140 °C oil bath overnight for complete activation.
(29) A rate for 1-pentanethiol (11) with Zr(NMe2)4 (5) is not obtainable
due to an immediate precipitation of deep blue complex. The mixture
of Zr(NMe2)4 (5) and benzylmercaptan (16) more slowly produces a
bright orange precipitate under identical conditions.
(30) Erker, G.; Froemberg, W.; Benn, R.; Mynott, R.; Angermund, K.;
Krueger, C. Organometallics 1989, 8, 911–920.
(31) Heyn, R. H.; Stephan, D. W. Inorg. Chem. 1995, 34, 2804–2812.
9
J. AM. CHEM. SOC. VOL. 132, NO. 30, 2010 10537

A R T I C L E S
Weiss and Marks
Figure 3. 1H NMR spectra in benzene-d6 of the dimer formed from reaction of benzylmercaptan (16) and Cp*ZrBn3 (2) during hydrothiolation of 1-hexyne
1
1
(6). Initial H NMR spectrum (500 MHz) of starting materials at 23 °C (A), H NMR spectrum (400 MHz) of reaction mixture at 120 °C with boadening
of signals of a and b (B), 1H NMR spectrum (400 MHz) after cooling to 60 °C (C), 1H NMR spectrum (400 MHz) after cooling to 23 °C (D), and the isolated
product (17, E).
bridging and terminal benzylthiolate ligands32 (Figure 3a,b)
along with free thiol (Figure 3d) is also verified by 1D NOESY
NMR spectroscopy. The known transoid [Cp*Zr(SEt)3]2 dimer31
(Figure 2B) with bridging ethanethiolates is also observed in
these studies by addition of ethanethiol to Cp*ZrBn3 (2). The
NMR data are in good agreement with literature values.31 Based
on the in situ observation of a N-H resonance in the 1H NMR
entries 3 and 6) evidence a 5× increase in rate, despite increased
steric encumberance. To assay electronic effects on the rates,
turnover frequencies of ethanethiol (7) and 2,2,2-trifluoroet-
hanethiol (9)34 were also measured and reveal no significant
fluorocarbon effects (Table 2, entries 1, 2).
Alkyne Effects on Hydrothiolation Rates. Alkyne structure
also affects the rate of hydrothiolation; however steric encum-
berance exhibits a less pronounced influence than electronic
characteristics. Switching from an R-monosubstituted to an
R-disubstituted alkyne results in a moderate decrease in rate
(Table 2, entry 1 and Table 3, entry 1 respectively). Product
formation with an R-trisubstituted alkyne (Table 3, entry 2) is
1
spectra of complex 1, the 3:1 H NMR integration of thiolate
to CGC ligands, and the known ability of thiols to displace
amide ligands from Zr(IV) complexes,33 we suggest that
coordination of the CGC ligand is predomimantly Cp-only in
the presence of excess thiol (eq 8).
1
observed by H NMR and GC/MS, although the yield is very
low. Similar to the aforementioned trend with thiols, alkyne
electronic characteristics also play a prominent role in influenc-
ing hydrothiolation rates, with conjugated alkynes exhibiting
significantly enhanced rates. In particular, introduction of
unsaturation R to the CtC bond results in a 5× rate increase
versus the unconjugated alkyne (Table 3, entries 1 and 5) while
phenylacetylene (30) increases the activity 4× versus the
cyclohexylacetylene (20) (Table 3, entries 1 and 6). Rate
enhancement is also observed with a 3-ethynylpyridine (32)
(Table 3, entry 7), although not as pronounced as that for phenyl
substitution (Table 3, entry 6).
Thiol Effects on Hydrothiolation Rates. Using CGCZrMe2
(1) as a representative precatalyst, a diverse group of thiols
offering variations in steric, electronic, and bonding energetic
characteristics was investigated in 1-hexyne (6) hydrothiolation.
Results are summarized in Table 2 and show that steric
encumberance is a major factor in determining the reaction
turnover frequency, with bulkier thiols exhibiting severely
retarded activity. In transitioning from a primary to a secondary
thiol (Table 2, entry 3 f 4), a greater than 50× rate reduction
is observed. No reactivity is observed with a tertiary thiol (Table
2, entry 5), presumably due to the increased nonbonding
repulsions. A comparison of primary thiol chain length effects
reveals a slight reduction in rate for 1-penthanethiol (11) f
ethanethiol (7) (Table 2, entries 1 and 3). Aromatic thiol
functionality also influences 1-hexyne (6) hydrothiolation rates
with the introduction of thiol phenyl groups markedly enhancing
the turnover frequencies. Thus, transitioning from cyclohexy-
lmercaptan (13) to thiophenol (18) (Table 2, entries 4 and 7)
results in a 20× increase in rate, while the turnover frequencies
of 1-pentanethiol (11) versus benzylmercaptan (16) (Table 2,
Reactivity and Selectivity Trends with Propargylamine. The
incorporation of an aliphatic amine functionality into the alkyne
substrate results in a dramatic hydrothiolation rate enhancement
with the degree of Markovnikov selectivity strongly dependent
on the structure of the precatalyst (Table 4). For propargylamine
(34), the substrate turnover frequency increases 3× and 7× with
Cp*ZrBn3 (2) and CGCZrMe2 (1) as precatalysts, respectively,
versus the corresponding 1-hexyne (6) hydrothiolation. While
Cp*ZrBn3 (2) yields the Markovnikov product (35) with 98%
selectivity (Table 4, entry 2), CGCZrMe2 (1) results in only
75% Markovnikov selectivity (Table 4, entry 2). The addition
of radical inhibitor γ-terpinene5i,11 with CGCZrMe2 (1) affords
no signifigant change in selectivity (Table 4, entry 3).35
(34) (a) Gregory, M. J.; Bruice, T. C. J. Am. Chem. Soc. 1960, 89, 2121–
2127. (b) Danehy, J. P.; Noel, C. J. J. Am. Chem. Soc. 1960, 82, 2511–
2515.
(32) Fritzinger, B.; Moreels, I.; Lommens, P.; Koole, R.; Hens, Z.; Martins,
J. C. J. Am. Chem. Soc. 2009, 131, 3024–3032.
(35) Additionally, 3-butyn-1-ol was tested together with 1-pentanethiol (11)
and compound 1. No hydrothiolation activity was observed.
(33) Chandra, G.; Lappert, M. F. J. Chem. Soc. A 1968, 1940–1945.
9
10538 J. AM. CHEM. SOC. VOL. 132, NO. 30, 2010

Markovnikov-Selective Intermolecular Hydrothiolation
A R T I C L E S
Table 2. Catalytic Organozirconium-Mediated Intermolecular Hydrothiolation of 1-Hexyne (6)
a Markovnikov selectivity determined by 1H NMR and CG/MS after 24.0 h in a 120 °C oil bath with 5 mol % 2 and a 3× molar excess of alkyne.
b Yield determined by 1H NMR with respect to thiol after 24.0 h in a 120 °C oil bath with 5 mol % 2 and a 3× excess of alkyne. c Turnover
frequencies measured in a 120 °C oil bath with 5 mol % 1 with a 1:1 alkyne:thiol ratio. d After 7 days in a 120 °C oil bath.
Radical Side Reactions. The observation of anti-Markovnikov
product isomers is reasonably attributed to a known, radical side
reaction4 (eq 1a) competing with the insertive/protonolytic
catalytic mechanism (see Discussion below). By adding the
radical inhibitor γ-terpinene,5i,11 the Markovnikov selectivity
of the reaction 6 + 11 f 12 mediated by 1 mol % 1 is increased
from 4:1 to 50:1 as assayed by 1H NMR and GC/MS. Further,
by increasing the catalyst concentration (Figure 4), Markovnikov
selectivity is furthur enhanced up to 99% (Figure 4). However,
neither high catalyst loadings nor radical inhibitor completely
eliminates the anti-Markovnikov products, indicating that some
may be due to imperfect, intrinsic catalytic selectivity.
the sequence of reaction events. Experiments were conducted
on the CGCZrMe2 (1)-mediated hydrothiolation of 1-hexyne (6)
by 1-pentanethiol (11), and kinetic results are plotted in Figure
5. The empirical rate law is derived by systematically varying
the concentration of CGCZrMe2 (1), 1-pentanethiol (11), and
1-hexyne (6) at 120 °C. Experiments carried out by varying
[CGCZrMe2 (1)] over the range 1.9-21 mM exhibit a clear,
linear trend when plotted against the measured rate (Figure 5B)
indicating a first-order dependence of rate on catalyst concentra-
tion. By varying [1-hexyne (6)] over the range 0.1-0.5 M, a
first-order trend is also observed in the plot of [1-hexyne (6)]
versus product formation rate (Figure 5C). The varying of
1-penthanethiol (11) concentration reveals a more complex
trend, with an approximate first-order behavior for [11] < 0.3
M, followed by saturation in the rate at concentrations > 0.3 M
(Figure 5D). As a result, the empirical rate law for the reaction
Kinetic and Mechanistic Studies of Organozirconium-Medi-
ated Alkyne Hydrothiolation. Kinetic studies were performed to
define the hydrothiolation reaction pathway and to better
understand the influence of [catalyst], [thiol], and [alkyne] on
9
J. AM. CHEM. SOC. VOL. 132, NO. 30, 2010 10539

A R T I C L E S
Weiss and Marks
Table 3. Catalytic Organozirconium-Mediated Intermolecular Alkyne Hydrothiolation by 1-Pentanethiol (11) as a Function of Alkyne
a
Markovnikov selectivity determined by H NMR and CG/MS after 24.0 h at 120 °C with 5 mol % 2 and a 3× excess of alkyne. b Yield determined
1
by H NMR with respect to thiol after 24.0 h in 120 °C with 5 mol % 2 and a 3× molar excess of alkyne. c Turnover frequencies measured in a 120 °C
1
d
1
oil bath with 5 mol % 1 with a 1:1 alkyne:thiol ratio. Hydrothiolation activity observed by H NMR and confirmed through GC/MS, although the yield
is very low. Quantitative by H NMR with respect to thiol. f With the addition of γ-terpinene radical inhibitor in a 1:1 molar ratio to alkyne.
e
1
6 + 11 f 12 is described by eq 9 with [CGCZrMe2 (1)] and
[1-hexyne (6)] both first-order, and [1-pentanethiol (11)] x-order
with x ) 1 for [1-pentanethiol (11)] e 0.3 M and x ) 0 for
[1-pentanethiol (11)] g 0.3 M. Additional catalyst- and alkyne-
dependence studies performed under high [thiol] conditions (i.e.,
[thiol] ) 1.2 M) show that [alkyne] and [catalyst] remain first-
order even at elevated [thiol].
and the data were plotted with respect to the Eyring equation.
Variable temperature studies at 0.2 M [alkyne] and [thiol]
result in an Eyring plot yielding ∆H‡ ) +18.1(1.2) kcal/
mol and ∆S‡ ) -20.9(2.5) e.u. Repeating the temperature
studies with [thiol] ) 1.2 M from 40 to 80 °C yields similar
reaction parameters of ∆H‡ ) +17.8(1.5) kcal/mol and ∆S‡
) -24.4(4.8) e.u.36
Rate ) kobs[CGCZr<]1[1-hexyne]1[1-pentanethiol]x (9)
To trace the fate of the DsCtCsR′ hydrogens in the present
catalytic transformations, deuterium-labeling experiments were
performed using deuterated phenylacetylene (30-d). Upon
addition of 1-penthanethiol (11) and 30-d to CGCZrMe2 (1) at
To derive activation parameters, the rate of the conversion
6 + 11 f 12 mediated by 1 was analyzed from 50 to 80 °C,
9
10540 J. AM. CHEM. SOC. VOL. 132, NO. 30, 2010

Markovnikov-Selective Intermolecular Hydrothiolation
A R T I C L E S
secondary kinetic isotope effect.40 At early reaction times, a
single olefinic resonance appears in the 1H NMR at δ 5.13 ppm
(Figure 6A) assigned to product 31-DE by 1D NOESY NMR.
In addition, 2H NMR shows a single product deuterium
resonance at δ 5.4 ppm. Upon furthur heating, additional product
Table 4. Catalytic Zirconocene-Mediated Intermolecular
Hydrothiolation of Propargylamine (34) with 1-Penthanethiol (11)
as a Function of Precatalyst
1
olefinic resonances appear in the H NMR spectra at δ 5.41,
5.40, and 5.14 ppm (Figure 6B-D) with a second olefinic
resonance in the 2H NMR at δ 5.1 ppm indicating the formation
of products 31, 31-DZ, and possibly 31-D2.41 Interestingly, a
deuterium resonance is also observed growing in at δ 1.07 ppm
indicating deuteration of the thiol (i.e., RSD).42,43 To further
examine the deuterium exchange from alkyne-d to thiol,
phenylacetylene-d (30-d), tert-butylmercaptan (15), and 1 were
dissolved in benzene-d6 and heated at 120 °C for 9 h. Despite
no evidence of zirconium-mediated hydrothiolation, deuterium/
proton exchange is observed by 1H and 2H NMR spectroscopy,
indicating that the exchange is independent of the zirconium-
mediated hydrothiolation pathway. A similar combination of
30-d and 11 without catalyst evidences no deuterium exchange
showing that zirconium is involved in the isotopic exchange
process.
Selectivity (%)
for 35
Nt
γ-Terpinene
Entry
Precatalyst
(h-1
)
Additiona
1
2
3
2, Cp*ZrBn3
1, CGCZrMe2
1, CGCZrMe2
98
75
76
4.8
No
No
Yes
4.7/3.3b
--
a Radical inhibitor was added in a 1:1 molar ratio to alkyne. b Initial
turnover frequency for anti-Markovnikov products (36-E/Z).
Discussion
Catalyst Ancillary Ligand Effects on Activity for Intermolecular
Terminal Alkyne Hydrothiolation. The choice of cyclopentadienyl
and other ligands has a critical effect on Zr-mediated hydrothi-
olation activity. The high activity observed with the
Cp*ZrCl2NMe2 (3) precatalyst is consistent with reported
organozirconium-mediated hydroamination rate enhancement by
chloride ligands.17b Given the large influence of thiol steric
characteristics on insertion kinetics, this possibly reflects
decongestion of the metal center, with the chlorides offering
less steric encumberance around the metal center versus
thiolates. Conversely, the slow activation and hydrothiolation
by Cp*2ZrMe2 (4) appears to be a result of severe, nonbonded
repulsions incurred by the bis(pentamethylcyclopentadieneyl)
ligation. Because of the predominantly Cp-based bonding of
the CGC ligand, differences in rate beteen CGCZrMe2 (1) and
Cp*ZrBn3 (2) are likely the result of optimal sterics or polar
interactions with the CGC amine functionality (see below).
Nature of Catalytic Species. Zirconium ancillary ligation
exerts dramatic effects on catalyst stability. First, the presence
of a cyclopentadienyl-based ligand avoids suspected, detrimental
catalyst aggregation31,44 and subsequent precipitation from
solution following the addition of excess thiol to the precatalyst.
Since no olefinic resonances are observed which would indicate
thiol C-S bond cleavage by the metal, as was reported by
Kanatzidis and co-workers,44 the precipitation is believed to be
the result of catalyst aggregation yielding insoluble thiolate
species.45 While mono-Cp* zirconium species are known in the
literature to undergo dimerization,32 Cp*2Zr(SR)2 species remain
monomeric.46 Therefore, the Cp-based ligands likely provide
steric protection from oligomerization to higher molecular
weight, insoluble species.
Figure 4. Plot of Markovnikov selectivity versus CGCZrMe2 (1) precatalyst
concentration for the transformation 6 + 11 f 12 (thiol:alkyne ) 1:1).
Data points show mol % catalyst versus substrate at fixed substrate
concentration.
room temperature, a single methane (CH4) resonance37 is
1
immediately observed in the H NMR spectrum (eq 10).
CGCZrMe2 + RSH + DsCtCR′ f [CGCZr(SR)2]n +
1
MesH (10)
The absence of CH3-D38 suggests exclusive activation of the
catalyst by thiol protonolysis despite known alkyne protonolysis
activity.39 To furthur rule out alkyne-mediated protonolysis as
a kinetically signifigant route for the cleavage of Zr-alkyl
bonds, relative rates of alkyne- and thiol-mediated protonolysis
were examined in the activation of Cp*2ZrMe2 (4). By addition
of either 1-hexyne (6) or 1-penthanethiol (11) to 4, thiol
protonolysis of the Zr-Me bonds is measured to be 150× more
rapid than the analogous alkyne protonolysis.
An apparent KIE of kH/kD ) 1.3(0.1) is measured for the
reaction 11 + 30-d catalyzed by complex 1, consistent with a
(36) For thermodynamic estimates, Eyring and Arrhenius plots, and kinetic
data at [Thiol] ) 1.2 M, see Supporting Information.
(37) Williams, L. A.; Marks, T. J. Organometallics 2009, 28, 2053–2061.
(38) Assayed by 2H and 1H NMR. The present study finds that CH3D gives
1
a triplet at 0.14 ppm in the H NMR.
(40) Tobisu, M.; Nakai, H.; Chatani, N. J. Org. Chem. 2009, 74, 5471–
5475.
(39) (a) Roering, A. J.; Maddox, A. F.; Elrod, L. T.; Chan, S. M.; Ghebreab,
M. B.; Donovan, K. L.; Davidson, J. J.; Hughes, R. P.; Shalumova,
T.; MacMillan, S. N.; Tanski, J. M.; Waterman, R. Organometallics
2009, 28, 573–581. (b) Hoyt, H. M.; Bergman, R. G. Angew. Chem.,
Int. Ed. 2007, 46, 5580–5582. (c) Nishiura, M.; Hou, Z. J. Mol. Catal.
A: Chem. 2004, 213, 101–106. (d) Wang, J.; Kapon, M.; Berthet, J. C.;
Ephritikhine, M.; Eisen, M. S. Inorg. Chim. Acta 2002, 334, 183–
192. (e) Dash, A. K.; Wang, J. Q.; Eisen, M. S. Organometallics 1999,
18, 4724–4741.
(41) In addition to NMR, the formation of 31 and 31-D(E/Z) are also
confirmed by HRMS. We are unable to support the formation of 31-
D2 by HRMS due to an overlapping 13C isotopic pattern.
(42) Stereochemical assignment of product vinyl proton resonances were
determined by 1D NOESY NMR spectroscopy. For 1D NOESY NMR
2
and H NMR spectra, see Supporting Information.
(43) Injecting ethanethiol-d (7-d) into a completed reaction did not result
in deuterium incorporation into an already formed product.
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J. AM. CHEM. SOC. VOL. 132, NO. 30, 2010 10541

A R T I C L E S
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Figure 5. A representative plot of product formation rate against time for CGCZrMe2 (1)-mediated hydrothiolation 6 + 11 f 12 (A). Plot of product
formation rate of 6 + 11 f 12 versus [CGCZrMe2 (1)] (B), [1-hexyne (6)] (C), and [1-pentanethiol (11)] (D) at [6] and [11] ) 0.2 M unless otherwise
indicated. All exhibit a first-order rate dependence on [catalyst] and [alkyne] at all explored concentrations and in [thiol] < 0.3 M. At [1-pentanethiol (11)]
> 0.3 M, the [thiol] dependence shifts to zero-order. The lines in plots A, B, and C are least-squares fits, whereas the line in D is a numerically fit to eq S4
with k1 ) 7 h-1 M-1, k-1 ) h-1, and k2 ) 20 h-1 M-1
.
zirconium-thiolate dimeric species are observed in the present
reaction media,32 the catalyst resting state is reasonably sug-
gested to be dimeric. Because the hydrothiolation rate is not
half-order in [catalyst], it is unlikely that the zirconium-thiolates
are involved in rapid dimer h monomer equilibriation prior to
entering the hydrothiolation cycle, as is the case for aggregated,
hydrothiolation-active, Pd and Ni complexes.5h,i,l This situation
stands in contrast to reported Rh and Me2SiCp″Th hydrothiolation-
active complexes which are proposed to be monomeric.5c,11,14a
DOSY47 NMR experiments were performed on the
[CGCZr(SR)3]n (R ) pentyl, ethyl, and benzyl) species in an
attempt to investigate the level of aggregation. However, due
to the ambiguous nature of the ligand amine coordination to
the zirconium center, reliable molecular volumes could not be
calculated for comparison to the experimental results.48 In the
present complexes, exchange between bridging and terminal49
thiolate ligands is also observed, along with evidence of
protonolytic exchange between free thiol and bound thiolate
ligands, indicating that the present zirconium-thiolate com-
plexes are labile and stereochemically dynamic in solution.
Figure 6. Hydrothiolation of 11 and 30-d yields multiple isotopomers with
deuterium incorporated in both the product E and Z positions. The 1H NMR
(500 MHz) spectrum in benzene-d6 evidences product 31-DE (5.13 ppm)
after 0.20 h in a 120 °C oil bath (A). Additional 31 (5.41/5.14 ppm) and
31-DZ (5.40 ppm) resonances are observed after heating for 0.50 h (B),
1.00 h (C), 7.66 h (D), and 40.2 h (E). Signal strengths are normalized to
an internal integration standard.
(44) Coucouvanis, D.; Hadjikyriacou, A.; Lester, R.; Kanatzidis, M. G.
Inorg. Chem. 1994, 33, 3645–3655.
(45) (a) Robertson, S. D.; Slawin, A. M. Z.; Woollins, J. D. Polyhedron
2006, 25, 823–826. (b) Friese, J. C.; Krol, A.; Puke, C.; Kirschbaum,
K.; Giolando, D. M. Inorg. Chem. 2000, 39, 1496–1500. (c) Ashby,
M. T.; Alguindigue, S. S.; Khan, M. A. Inorg. Chem. Acta 1998, 270,
227–237.
Given the tendency of zirconium-thiolates to undergo ag-
gregation and that previously reported [Cp*Zr(µ-SR)(SR)2]2
(46) Howard, W. A.; Trnka, T. M.; Parkin, G. Inorg. Chem. 1995, 34, 5900–
5909.
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10542 J. AM. CHEM. SOC. VOL. 132, NO. 30, 2010

Markovnikov-Selective Intermolecular Hydrothiolation
A R T I C L E S
Scheme 2. A π-Interaction Drawing Away the Thiol Substituent (E)
To Reduce Steric Interference during Alkyne Insertion (F) and
Stabilize the Electrophilic Metal Center in the Insertive Transition
State
Substrate Scope for Catalytic Intermolecular Terminal
Alkyne Hydrothiolation. As can be seen from the data in Tables
2 and 3, cyclopentadienyl zirconium complexes are efficient
precatalysts for transforming a wide range of thiols and terminal
alkynes into vinyl sulfides with a high degree of Markovnikov
selectivity. While many late-metal hydrothiolation catalysts can
effect this transformation with arylthiols at varying levels of
efficiency,2a,5c-o,8b few are effective with less reactive aliphatic
thiols.5c,d,i,m,50 In contrast, the present organozirconium com-
plexes 1-4 are able to mediate hydrothiolation with aliphatic,
benzylic, and aromatic thiols for the intermolecular, homoge-
neous hydrothiolation of a wide variety of terminal aliphatic,
benzylic, and aromatic alkynes.
Scheme 3. Proposed Insertive Transition States for the Formation
Thiol steric characteristics appear to be the dominant factor
governing catalytic activity here, with secondary and tertiary
thiols severely retarding hydrothiolation rates. This large rate
dependence on nonbonded repulsions is consistent with multiple
thiolate ligands45b,c,51 offering substantial steric congestion
around the metal center as the alkyne insertion transition state
is traversed. The thiol electronic characteristics also have a
signifigant effect on the hydrothiolation turnover frequency, with
the aromatic and benzylic thiols exhibiting the greatest activity.
With no appreciable difference in rate between ethanethiol (7)
and 2,2,2-trifluoroethanethiol (9), it can be concluded that alkyl
electronic factors have less influence on catalytic turnover.
Therefore, the rate enhancement observed as a result of the
aromaticity is not likely due to electronic effects at the sulfur
atom. One scenerio invokes π-interaction of the arene with the
electrophilic zirconium center.10g,52 This may lower the alkyne
insertion barrier by π-electron stabilization of the electrophilic
metal center8g,10g,53 (Scheme 2, E) or possibly reducing steric
encumberance at the metal center by restraining the thiol
substituent (Scheme 2, F).
In contrast to thiols, alkyne steric factors have a lesser effect
on the observed rates, with an R-monosubstituted alkyne
exhibiting 1.5× the hydrothiolation rate of a similar R-disub-
stituted alkyne (Tables 2 and 3, entries 3 and 1, respectively).
These observations are in agreement with turnover-limiting
insertion of the alkyne into the Zr-SR bond where bulkier
alkynes are expected to congest the metal coordination sphere
in the turnover-limiting step to a lesser degree than analogous
thiols. This likely reflects orientation of the alkyne substituent
away from the bulky metal ligation (see below), with each
of Markovnikov (G) and Anti-Markovnikov Hydrothiolation Products
(H)
zirconium center coordinated to three thiolate ligands versus
presumably only a single alkyne involved in the insertive
transition state. Furthermore, alkyne substituent electronic
characteristics significantly affect hydrothiolation activities with
the effects more pronounced for alkynes than for thiols. As
observed with late transition metal5c,l,m and organothorium
catalysts,11 3-5× rate increases are observed as a result of
conjugation or aromaticity R to the CtC linkage (Table 3, 20
f 28, 30, 32), possibly the result of the π-system electron-
withdrawing nature rendering the acetylene more electrophilic.
Regioselectivity of Intermolecular Terminal Alkyne Hydrothi-
olation. The present catalytic system is able to effect hydrothi-
olation processes with up to 99% Markovnikov selectivity and
with no observable side products other than the occasional
aforementioned anti-Markovnikov vinyl sulfides. An interplay
of electronic and nonbonding repulsion in the four-membered
insertive transition state is likely responsible for the high
Markovnikov selectivity observed (Scheme 3). Reminiscent of
lanthanide-mediated hydroamination,8g,53 the Markovnikov ori-
entation of the acetylene with respect to the Zr-SR bond is
expected to stabilize the electrophilic metal center in the
transition state by placing greater electron density on the
acetylene R carbon atom (Scheme 3, G). In addition, orientation
of the R′ substituent away from the bulky supporting ligation
doubtlessly minimizes energetically unfavorable, nonbonding
interactions (Scheme 3, H).
(47) (a) Floquet, S. b.; Brun, S. b.; Lemonnier, J.-F.; Henry, M.; Delsuc,
M.-A.; Prigent, Y.; Cadot, E.; Taulelle, F. J. Am. Chem. Soc. 2009,
131, 17254–17259. (b) Li, D.; Kagan, G.; Hopson, R.; Williard, P. G.
J. Am. Chem. Soc. 2009, 131, 5627–5634. (c) Busetto, L.; Cassani,
M. C.; Femoni, C.; Macchioni, A.; Mazzoni, R.; Zuccaccia, D. J.
Organomet. Chem. 2008, 693, 2579–2591. (d) Bellachioma, G.;
Ciancaleoni, G.; Zuccaccia, C.; Zuccaccia, D.; Macchioni, A. Coord.
Chem. ReV. 2008, 252, 2224–2238. (e) Pianet, I.; Andre´, Y.; Ducasse,
M.-A. s.; Tarascou, I.; Lartigue, J.-C.; Pinaud, N. l.; Fouquet, E.;
Dufourc, E. J.; Laguerre, M. Langmuir 2008, 24, 11027–11035. (f)
Macchioni, A.; Ciancaleoni, G.; Zuccaccia, C.; Zuccaccia, D. Chem.
Soc. ReV. 2008, 37, 479–489.
While anti-Markovnikov side products are occasionally
observed in the present hydrothiolation reactions, they are not
typically the result of organozirconium-centered catalytic reac-
tions but rather arise from known, free radical side reactions.4
These competing processes can be suppressed by addition of
(48) (a) La-Scalea, M. A.; Menezes, G. M. S.; Ferreira, E. I. THEOCHEM
2005, 730, 111–120. (b) Zuccaccia, C.; Stahl, N. G.; Macchioni, A.;
Chen, M.-C.; Roberts, J. A.; Marks, T. J. J. Am. Chem. Soc. 2004,
126, 1448–1464.
(49) (a) Sirimanne, C. T.; Yu, Z.; Heeg, M. J.; Winter, C. H. J. Organomet.
Chem. 2006, 691, 2517–2527. (b) Ashworth, N. J.; Conway, S. L. J.;
Green, J. C.; Green, M. L. H. J. Organomet. Chem. 2000, 609, 83–
88. (c) Thompson, R. L.; Lee, S.; Geib, S. J.; Cooper, N. J. Inorg.
Chem. 1993, 32, 6067–6075.
(52) (a) Kissounko, D.; Epshteyn, A.; Fettinger, J. C.; Sita, L. R.
Organometallics 2006, 25, 531–535. (b) O’Connor, P. E.; Morrison,
D. J.; Steeves, S.; Burrage, K.; Berg, D. J. Organometallics 2001, 20,
1153–1160. (c) Bouwkamp, M.; van Leusen, D.; Meetsma, A.; Hessen,
B. Organometallics 1998, 17, 3645–3647. (d) Cardin, C. J.; Cardin,
D. J.; Morton-Blake, D. A.; Parge, H. E.; Roy, A. Dalton Trans. 1987,
7, 1641–1645.
(50) This diminished activity has been attributed to the greater H-S bond
enthalpies; see ref 5i.
(51) Fandos, R.; Lanfranchi, M.; Otero, A.; Pellinghelli, M. A.; Ruiz, M. J.;
Terreros, P. Organometallics 1996, 15, 4725–4730.
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A R T I C L E S
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Scheme 4. Transition States for the Markovnikov (I) and
Anti-Markovnikov (J) Insertion of Propargylamine into a Zr-SR
Bond
Scheme 5. Propargylamine (34) Orientations for the Formation of
Markovnikov (K) and Anti-Markovnikov Products (L)
As is apparent below, the activation parameters for the present
transformation generally parallel analogous insertions of un-
saturations into LnM-E (E ) N, O, S) bonds where LnM ) a
group 4 or f-element center. The larger ∆H‡ compared to
organozirconium-mediated hydroamination (Table 5, entry 4)
is consistent with a stronger Zr-SR bond enthalpy imposing a
greater barrier for insertion.58 The negative ∆S‡ indicates a
highly ordered transition state; however, the magnitude is more
consistent with intramolecular processes indicating reduction
in the degrees of freedom as the insertive transition state is
traversed.
the radical inhibitor, γ-terpinene (Figure 2).54 For example, the
formation of anti-Markovnikov products in the 6 + 11 f 12
transformation is suppressed by 10× through addition of the
radical inhibitor (Figure 4). Furthermore, from the observation
of greater Markovnikov selectivity with increased catalyst
concentrations (Figure 5), it can be concluded that the orga-
nozirconium complex is not involved in radical generation or
propagation processes, but rather Zr-centered catalytic turnover
is in kinetic competition with the radical-mediated side reaction.
Because the same anti-Markovnikov products are also observed
in the absence of organozirconium complexes,55 the radical
process can clearly be initiated in the absence of the organo-
metallic catalyst.
The present variation in Markovnikov selectivities for dif-
ferent substrates is found to be largely a function of the
organometallic catalyst-mediated process competing with radical
hydrothiolation.4 As is the case for substrate 13 (Table 2), low
selectivity correlates with the inability of the sluggish catalytic
reaction to effectively outrun the competing radical process.
Other differences in selectivity result from varying substrate
reactivities with respect to radical hydrothiolation. For example,
conjugated alkynes (e.g., Table 3, entry 5) evidence lower
hydrothiolation selectivities, possible the result of resonance
stabilization of the postaddition radical intermediate.4
Because γ-terpinene addition does not appreciably suppress
anti-Markovnikov products in the 34 + 11 f 35 transformation,
the low selectivity of CGCZrMe2 (1)-catalyzed hydrothiolation
of propargylamine (34) is unlikely the result of a radical side
reaction. Preferential reduction in transition state energy by
amine precoordination to the metal center56 may contribute to
the observed enhanced activity and reduced selectivity (Scheme
4); however, this fails to adequately explain the high selectivity
observed with Cp*ZrBn3 (2) as the catalyst. One possible
explanation is hydrogen bonding between the amine functional-
ity of substrate 34 and the CGC ligand HN group whereby the
alkyne functionality is held in an anti-Markovnikov orientation57
for subsequent insertion into the Zr-SR bond (Scheme 5, L).
Activation Parameters. Through variable temperature kinetic
studies, the activation parameters for CGCZrMe2 (1)-mediated
6 + 11 f 12 are summarized below (Table 5, entry 1) along
with previously reported activation parameters for analogous
intramolecular and intermolecular hydroelementation processes.
Kinetics and Mechanism of Intermolecular Hydrothiolation
of Terminal Alkynes. A summary of organozirconium-mediated
alkyne hydrothiolation observables and kinetic data is presented
below, as a prelude to further mechanistic discussion.
1. Empirical rate law: Rate ) kobs[Zr]1[alkyne]1[thiol]x, x )
0-1
2. High Markovnikov selectivity
3. Observed zirconium-thiolate complexes present in the
reaction media
4. Activity dramatically influenced by increased thiol en-
cumberance and moderately by alkyne encumberance
5. Activation parameters consistent with turnover-limiting
insertion processes
6. Alkyne isotopic labeling yields kH/kD ) 1.3(0.1)
7. Single product isotopomer formation early in the reaction
8. Deuterium scrambling between alkyne and thiol
9. Gradual formation of multiple product isotopomers as the
reaction progresses.
Rapid catalyst activation (i.e., Zr-Me and Zr-Bn bond
cleavage) is observed with the addition of thiol as indicated by
the formation of methane or toluene in the 1H NMR. In
deuterium-labeling studies with deuterated alkyne and nondeu-
terated thiol, the exclusive observation of CH4 during CGC-
ZrMe2 (1) activation evidences that thiol-induced Zr-CH3
protonolysis is operative and the exclusive or dominant pathway
for catalyst activation under reaction conditions (eq 9). This is
despite literature reported alkyne-mediated protonolysis39,52a of
similar Zr-C bonds and is quantified by thiol-mediated proto-
nolysis measuring 150× faster than analogous alkyne-mediated
protonolysis of Zr-Me bonds in the present study. In addition,
the detection of zirconium-thiolate species in solution support
a thiolate catalyst resting state, while observed zirconium-thiolate
dimers in the reaction medium suggest instances of dimeric
catalyst resting states and possible aggregated, hydrothiolation-
active species.
(53) (a) Horton, A. D.; Orpen, A. G. Organometallics 1991, 10, 3910–
3918. (b) Burger, B. J.; Thompson, M. E.; Cotter, W. D.; Bercaw,
J. E. J. Am. Chem. Soc. 1990, 112, 1566–1577.
The kinetics, deuterium labeling, observation of zirconium-
thiolates, and the high degree of Markovnikov regioselectivity
are consistent with an alkyne insertion pathway. This is
analogous to organoactinide-mediated hydrothiolation,11 where
(54) γ-Terpinene is added in equimolar quantities to alkyne.
(55) Silva, M. S.; Lara, R. G.; Marczewski, J. M.; Jacob, R. G.; Lenarda˜o,
E. J.; Perin, G. Tetrahedron Lett. 2008, 49, 1927–1930.
(56) (a) Shen, H.; Chan, H.-S.; Xie, Z. Organometallics 2008, 27, 1157–
1168. (b) Guerin, F.; McConville, D. H.; Vittal, J. J.; Yap, G. A. P.
Organometallics 1998, 17, 5172–5177. (c) Walsh, P. J.; Hollander,
F. J.; Bergman, R. G. J. Organomet. Chem. 1992, 428, 13–47.
(57) Shibasaki, M.; Yoshikawa, N. Chem. ReV. 2002, 102, 2187–2210.
(58) Nolan, S. P.; Stern, D.; Marks, T. J. J. Am. Chem. Soc. 1989, 111,
7844–7853.
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Markovnikov-Selective Intermolecular Hydrothiolation
A R T I C L E S
Table 5. Activation Parameters for Hydrothiolation, Hydroalkoxylation, and Hydroamination Processes
a Determined using Me2SiCp′′2Th(CH2TMS)2 as a precatalyst.11 b Determined using CGCU(NMe2)Cl as a precatalyst.17b c Determined using
CGCZr(NMe2)Cl as
a a a
precatalyst.17b d Determined using Me2SiCp′′2NdCH(TMS)2 as precatalyst.8l e Determined using La[N(TMS)2]3 as
precatalyst.10k
Scheme 6. Proposed Turnover-Limiting Alkyne Insertion Pathway for Organozirconium-Mediated Terminal Alkyne Hydrothiolation Mediated
by a Representative Monomeric Organozirconium Complex62
the acetylene undergoes insertion into the Zr-SR bond, followed
by thiol-mediated protonolysis to yield product and regenerate
the catalyst. Alkynes were previously reported to undergo
π-bond metathesis with ZrdS double bonds (eq 11)59 to generate
isolable species; however, CtC insertion into a ZrsSR σ-bond
necessity to maintain the CsS bond61,44 requires the formation
of a zwitterionic species, which is inconsistent with the
negligible observed rate difference between ethanethiol (7) and
2,2,2-trifluoroethanethiol (9) hydrothiolation, despite different
electronic characteristics. Therefore, we propose that the alkyne
undergoes direct insertion into a ZrsSR σ-bond with no
competing ZrsS/ZrdS equilibrium (Scheme 6, k1).
In the hydrothiolation of 30-d, the initial observation of
product 31-DE furthur supports an insertion pathway with
subsequent thiol-mediated, protonolytic product formation (eq
12). Interestingly, deuterium exchange between the alkyne and
has not, to the best of our knowledge, been reported until now.
An equilibrium between a ZrsSR σ-bond and an insertion-
inactive Zr(-)dS(+)R species similar to that observed with
zirconium-phosphides60 and in analogous organozirconium-
mediated hydroamination8m,17b can be envisioned. However the
(60) Hou, Z.; Breen, T. L.; Stephan, D. W. Organometallics 1993, 12, 3158–
3167.
(61) Organozirconium complexes are known from the literature to cleave
thiol C-S bonds; however, corresponding alkene products, indicative
1
of this process, were not been observed by H NMR or GC/MS.
(59) (a) Carney, M. J.; Walsh, P. J.; Hollander, F. J.; Bergman, R. G.
Organometallics 1992, 11, 761–777. (b) Carney, M. J.; Walsh, P. J.;
Bergman, R. G. J. Am. Chem. Soc. 1990, 112, 6426–6428.
(62) The catalytic cycle is presented here with a monomeric organozirco-
nium complex for simplicity. See Supporting Information for a dimer
catalytic cycle.
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A R T I C L E S
Weiss and Marks
thiol as the reaction progresses eventually results in the
formation products 31, 31-DZ, and 31-D2. A control experiment
are the rate constants for the insertion/extrusion of alkyne into
the Zr-SR bond, and k2 is the rate constant for thiol-mediated
protonolysis of product from the metal center (see Scheme 6).64
Consistent with the observed rate law (eq 8), the derived rate
equation shows thiol and alkyne are approximately first-order
at lower concentrations and the catalyst to be first-order at all
concentrations. As [thiol] increases, the reaction rate remains
first-order in catalyst and alkyne and becomes zero-order in
[thiol] (Figure 6; eq 16). Alkyne does not become zero-order
over the investigated concentration ranges since thiol proto-
nolysis is far more rapid than alkyne insertion (i.e., k1 < k2)
and k-1 is small. Equation 15 can be fit to Figure 6 with k1 )
combining 30-d and 11 without catalyst evidences no deuterium
exchange, indicating that the scrambling of the isotopic labeling
is zirconium-mediated and not a radical process. While alkyne-
mediated protonolysis of the insertion product from the metal
center is a possible source of deuterium migration to the alkyne
(e.g., eq 13), this pathway is not believed significant since
1-mediated deuterium swapping occurs between 15 and 30-d
7 h-1 M-1, k-1 ) 1 h-1, and k2 ) 20 h-1 M-1
.
k1k2[Zr][Thiol][Alkyne]
Rate )
(15)
k1[Alkyne] + k-1 + k2[Thiol]
Rate ≈ k1[Catalyst][Alkyne] for [Thiol] .
[Alkyne] (16)
without observable insertion. Therefore, we propose that a
zirconium-thiolate/zirconium-alkynyl protonolysis/deuterolysis
side equilibrium is operative (e.g., eq 14). Because thiol-
mediated Zr-C protonolysis is orders of magnitude faster than
the analogous alkyne-mediated protonolysis and no zirconium-
alkynyl63 species is observed via NMR, this equilibrium is
believed to strongly favor the zirconium-thiolate and is therefore
kinetically insignificant to the catalytic cycle.
Conclusions
The catalytic, organozirconium-mediated, intermolecular hy-
drothiolation of a wide range of terminal alkynes by aliphatic,
benzylic, and aromatic thiols has been explored in terms of scope
and mechanism. The ready availability of these zirconium
complexes along with their high Markovnikov selectivities and
efficacy with less reactive aliphatic thiols makes them an
attractive alternative to many hydrothiolation catalysts. The
activation parameters ∆S‡ and ∆H‡ were determined through
variable-temperature studies and suggest a highly ordered
transition state and an activation energy consistent with analo-
gous hydroelementation processes. Based on kinetic data, the
reaction is proposed to proceed through an alkyne insertion-thiol
protonolysis sequence with turnover-limiting alkyne insertion.
Acknowledgment. The National Science Foundation (CHE-
0809589) is gratefully acknowledged for financial support of this
research. We also thank Dr. A. Atesin, Mr. S. Wobser, and Mr. M.
Weberski for helpful discussions.
To test for a change in the turnover-limiting step in Scheme
6 when [thiol] > 0.3 M, variable temperature studies were
performed with [thiol] at 1.2 M from 40 to 80 °C. The resulting
activation parameters for [thiol] ) 0.2 and 1.2 M are within
modest margins of uncertainty, implying a common turnover-
limiting step. This result thus supports a turnover-limiting alkyne
insertion followed by a more rapid, thiol-mediated protonolysis
at all investigated [thiol]. Regarding the interpretation of the
kinetic data at lower [thiol], while the protonolysis is still more
rapid than alkyne insertion, it is kinetically relevant to the overall
rate of hydrothiolation. This situation is similar to an analogous
lanthanide hydrophosphination9c,f-h where protonolysis of
intermediate metal-alkyl species is slow enough to be kineti-
cally observable. With increasing [thiol] in the present case,
the protonolysis is accelerated until alkyne insertion into the
Zr-SR bond becomes the only kinetically relevant step of the
overall reaction. This scenario can be modeled by the steady-
state approximation (see Supporting Information for details) (eq
15) where alkyne insertion is turnover-limiting, where k1/k-1
Supporting Information Available: Product characterization,
kinetic equation derivations, NMR spectra, thermodynamic
calculations, and kinetic data. This material is available free of
charge via the Internet at http://pubs.acs.org.
JA103979B
(63) (a) Ugolotti, J.; Kehr, G.; Fro¨hlich, R.; Grimme, S.; Erker, G. J. Am.
Chem. Soc. 2009, 131, 1996–2007. (b) Albert, B. J.; Koide, K. J. Org.
Chem. 2008, 73, 1093–1098. (c) Rosenthal, U.; Ohff, A.; Baumann,
W.; Kempe, R.; Tillack, A.; Burlakov, V. V. Angew. Chem., Int. Ed.
Engl. 1994, 33, 1605–1607.
(64) Protonolysis is typically rapid in reports of organozirconium- and
organo-f-element-mediated hydroelementation (refs 8h,n); however,
organolanthanide-catalyzed hydrophosphination (refs 9f-h) appears
to have a more sluggish product protonolysis from the metal center,
resulting in turnover-limiting protonolysis.
9
10546 J. AM. CHEM. SOC. VOL. 132, NO. 30, 2010