N-Substituted Derivatives of the Azadithiolate Cofactor from the [FeFe] Hydrogenases: Stability and Complexation

Article abstract of DOI:10.1021/acs.inorgchem.5b00290

Experiments are described that probe the stability of N-substituted derivatives of the azadithiolate cofactor recently confirmed in the [FeFe] hydrogenases (Berggren, G., et al. Nature 2013, 499, 66). Acid-catalyzed hydrolysis of bis(thioester) BnN(CH

Full text of DOI:10.1021/acs.inorgchem.5b00290

Article
pubs.acs.org/IC
N‑Substituted Derivatives of the Azadithiolate Cofactor from the
[FeFe] Hydrogenases: Stability and Complexation
Raja Angamuthu,† Chi-Shian Chen, Tyler R. Cochrane, Danielle L. Gray, David Schilter, Olbelina A. Ulloa,
and Thomas B. Rauchfuss*
School of Chemical Sciences, University of Illinois at Urbana−Champaign, Urbana, Illinois 61801, United States
S
* Supporting Information
ABSTRACT: Experiments are described that probe the stability
of N-substituted derivatives of the azadithiolate cofactor recently
confirmed in the [FeFe] hydrogenases (Berggren, G., et al.
Nature 2013, 499, 66). Acid-catalyzed hydrolysis of bis(thioester)
BnN(CH2SAc)2 gives [BnNCH2SCH2]2 rather than azadithiol
BnN(CH2SH)2. Treatment of BnN(CH2SAc)2 with NaOtBu
generates BnN(CH2SNa)2, which was trapped with NiCl2(diphos) (diphos = 1,2-C2H4(PR2)2; R = Ph (dppe) and Cy (dcpe)) to
give fully characterized complexes Ni[(SCH2)2NBn](diphos). The related N-aryl derivative Ni[(SCH2)2NC6H4Cl](diphos) was
prepared analogously from 4-ClC6H4N(CH2SAc)2, NaOtBu, and NiCl2(dppe). Crystallographic analysis confirmed that these
rare nonbridging [adtR]2− complexes feature distorted square planar Ni centers. The analogue Pd[(SCH2)2NBn](dppe) was also
prepared. 31P NMR analysis indicates that Ni[(SCH2)2NBn](dppe) has basicity comparable to typical amines. As shown by
cyclic voltammetry, the couple [M[(SCH2)2NBn](dppe)]+/0 is reversible near −2.0 V versus Fc+/0. The wave shifts to −1.78 V
upon N-protonation. In the presence of CF3CO2H, Ni[(SCH2)2NBn](dppe) catalyzes hydrogen evolution at rate of 22 s−1 in the
acid-independent regime, at room temperature in CH2Cl2 solution. In contrast to the instability of RN(CH2SH)2 (R = alkyl,
aryl), the dithiol of tosylamide TsN(CH2SH)2 proved sufficiently stable to allow full characterization. This dithiol reacts with
Fe3(CO)12 and, in the presence of base, NiCl2(dppe) to give Fe2[(SCH2)2NTs](CO)6 and Ni[(SCH2)2NTs](dppe),
respectively.
double resonance studies on [FeFe] hydrogenases that revealed
coupling of Fe(I) to two 14N centers, proposed to be the CN−
cofactor and the azadithiolate bridge.8 This assignment is
supported by recent work on the C15N-enriched enzyme.9,10
The nature of the dithiolate has finally been settled, with
experiments showing that synthetic [Fe2[(SCH2)2NH]-
(CN)2(CO)4]2− reconstitutes apo-HydA1 from C. reinhardtii
to give a highly active catalyst. Isostructural diiron complexes
[Fe2(S2C3H6)(CN)2(CO)4]2− and [Fe2[(SCH2)2O]-
(CN)2(CO)4]2− are also accepted by the apoenzyme,11,12 but
the resulting proteins exhibit very low catalytic activity.12
Now that the azadithiolate cofactor has been confirmed, it is
of interest to examine the cofactor itself, free of the protein and,
if possible, metals. First reported in 2001,13 complexes of
[adtR]2− can be prepared by many routes, almost all of which
involve installation of the cofactor on diiron centers (Scheme
INTRODUCTION
■
The identity of the dithiolate cofactor that supports the activity
of the [FeFe] hydrogenases has been actively discussed since
the original crystallographic descriptions of the enzymes1 from
D. desulfuricans and C. pasteurianum. Model studies show that
the amine in azadithiolates facilitates protonation of its
Fe(I)Fe(I) derivatives (Figure 1).2,3 Furthermore, amine-
Figure 1. Active site of the H-cluster in [FeFe] hydrogenase enzyme
(left) and typical model complex (right).
1).13−16 Typical routes include condensation of CH2O and
14,16
amines with Fe2(SH)2(CO)6
and alkylation of Fe2(μ-
SLi)2(CO)6, the latter route only suited for tertiary amines of
containing dithiolates are required for oxidation of H2 by
mildly electrophilic Fe(II)Fe(I) species.4 The idea5 of an amine
poised close but not coordinated to a metal center has spawned
the development of homogeneous catalysts featuring proton
relays6 and is a foundation of our understanding of the second
coordination sphere.7
the type RN(CH2Cl)2.13 Related complexes have been
17
2−
developed with an azadiphosphide group (RN(CH2PR)2
)
18
2−
and a azadiselenide (RN(CH2Se)2
centers.
)
bridging two iron
The first spectroscopic evidence for the azadithiolate cofactor
versus, say, 1,3-propanedithiolate, came from electron−nuclear
Received: February 6, 2015
© XXXX American Chemical Society
A
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Scheme 1. Synthetic Routes to Fe2[(SCH2)2NR](CO)6
In terms of obtaining the free cofactor, the diiron dithiolates
represent obvious precursors to RN(CH2SH)2. Azadithiolato
diiron complexes are, however, robust and exhibit no tendency
to release the cofactor even in the presence of strong acids.
Free HN(CH2SH)2 and related derivatives might be
anticipated to be unstable with respect to loss of hydrogen
sulfide. This anticipated reactivity necessitates that the
azadithiolates or their protonated derivatives be generated
under mild reaction conditions. The bis(thioester) compounds
of type RN(CH2SAc)2 emerged as attractive precursors to the
azadithiolates. Indeed, hydrolysis of one such thioester has been
claimed to afford [HOC2H4N(H)(CH2SH)2]Cl, the conjugate
acid of an azadithiol.19
with Fe3(CO)12 gave complex mixtures containing only traces
of Fe2[(SCH2)2NBn](CO)6.
Trapping RN(CH2SNa)2 (R = Bn or 4-ClC6H4). Given the
instability of azadithiol RN(CH2SH)2 implicated by the
previous experiments, the preparation of the corresponding
dithiolate dianion was investigated. Treatment of BnN-
(CH2SAc)2 with NaOMe in MeOH afforded mainly the
known diether BnN(CH2OMe)2. A bulkier nucleophile might
favor attack at the carbonyl centers instead of the methylene
groups, and avoidance of protic solvents would preclude
formation of any thiols, these being prone to the degradation
pathway in eq 3. Indeed, experiments suggest that the dithiolate
can be generated by treatment of RN(CH2SAc)2 (R = Bn, 4-
ClC6H4) with NaOtBu in tetrahydrofuran (THF) at −78 °C.
The putative RN(CH2SNa)2 was derivatized by treatment with
NiCl2(diphos) (diphos = 1,2-C2H4(PR′2)2; R′ = Ph (dppe) and
Cy (dcpe)). These trapping experiments afforded modest yields
of orange microcrystalline solids identified as Ni[(SCH2)2NR]-
(diphos) (eqs 4 and 5).
RESULTS AND DISCUSSION
■
Preparation and Hydrolysis of BnN(CH2SAc)2. Hydrox-
ymethylation of primary amines in the presence of thioacetic
acid is known to efficiently give bis(thioesters) RN-
(CH2SAc)2.20 The relevant transformations are given in eqs 1
and 2.
RN(CH2SAc)2 + 2NaOtBu
t
RNH2 + 2CH2O → RN(CH2OH)2
(1)
→ 2BuOAc + RN(CH2SNa)2
(4)
RN(CH2OH)2 + 2AcSH → RN(CH2SAc)2 + 2H2O
RN(CH2SNa)2 + NiCl2(diphos)
(2)
→ Ni[(SCH2)2NR](diphos) + 2NaCl
(5)
This method appears general, and the initial phases of this
study focused on benzyl derivatives. The acid-catalyzed
hydrolysis of BnN(CH2SAc)2 was investigated as a route to
the dithiol BnN(CH2SH)2. Upon treatment with aqueous HCl
in EtOH, BnN(CH2SAc)21 was rapidly consumed with
formation of a precipitate. H NMR analysis of the crude
product with an internal standard showed that
[BnNCH2SCH2]2 was present in ∼60% yield. The reaction
does not yield NMR-detectable amounts of trithiane (SCH2)3,
a result consistent with the stoichiometry in eq 3.
In the case of the electrophile NiCl2(dppe), the derivative
Ni[(SCH2)2NR](dppe) was isolated and characterized accord-
1
ing to H and 31P{1H} NMR and electrospray ionization mass
spectrometry (ESI-MS) data. The complexes were stable as
solids and in THF, CH2Cl2, and MeCN solution under an inert
atmosphere. Single crystals of Ni[(SCH2)2NR](dppe) were
grown from CH2Cl2/pentane. The solid-state structures of the
two compounds are presented in Figures 2 and 3.
Crystallographic analysis revealed that Ni[(SCH2)2NBn]-
(dppe) features a twisted NiS2P2 coordination. The average
Ni−S (2.185 Å) and Ni−P bond lengths (2.176 Å) are similar
to those in the propanedithiolate Ni(S2C3H6)(dppe) (2.203
and 2.160 Å, respectively).22 Substitution, however, of CH2
with NBn causes distortion of the ligand environment such that
the NiS2 and NiP2 planes in Ni[(SCH2)2NBn](dppe) are
twisted by 19.6° (this value being 7.6° for the propane-
dithiolate). In the crystal, the Bn group participates in weak
edge-to-face π−π stacking (4.3 Å) with the dppe ligand of a
neighboring complex, orienting Bn toward Ni. In addition to
2BnN(CH2SAc)2 + 2H2O
→ [BnNCH2SCH2]2 + 2H2S + 4HOAc
(3)
Experiments were conducted testing the utility of
[RNCH2SCH2]2 and the bis(thioesters) as precursors to diiron
azadithiolate complexes. Reaction of [RNCH2SCH2]2 with
Fe3(CO)12 yields Fe2(SCH2N(R)CH2)(CO)6 instead of the
typical Fe2[(SCH2)2NBn](CO)6 derivatives featuring Fe2S2
tetrahedranes.21 Additionally, reaction of BnN(CH2SAc)2
B
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Figure 2. ORTEP of Ni[(SCH2)2NBn](dppe) with ellipsoids drawn at
the 50% probability level. H atoms and disorder are omitted for clarity.
Selected distances (Å): Ni1−S1, 2.1925(10); Ni1−S2, 2.1766(9);
Ni1−P1, 2.1840(10); Ni1−P2, 2.1675(9). Selected angles (deg): S1−
Ni1−S2, 100.46(3); P1−Ni1−P2, 85.84(3); P1−Ni1−S1, 165.05(3);
P2−Ni1−S1, 88.93(3); P1−Ni1−S2, 88.20(3); P2−Ni1−S2,
163.16(3); C27−N1−C28, 112.8(2), C27−N1−C29, 114.6(3);
C28−N1−C29, 113.7(2).
Figure 4. ORTEP of Ni[(SCH2)2NBn](dcpe)·CH2Cl2, showing one
of the crystallographically independent complexes with ellipsoids
drawn at the 50% probability level. H atoms, solvate, and disorder are
omitted for clarity. Selected distances (Å): Ni1−S1, 2.1952(19); Ni1−
S2, 2.1841(18); Ni1−P1, 2.1884(18); Ni1−P2, 2.1866(18); Ni2−S3,
2.1860(19); Ni2−S4, 2.176(2); Ni2−P3, 2.1774(19); Ni2−P4,
2.1797(18). Selected angles (deg): S1−Ni1−S2, 100.01(7); P1−
Ni1−P2, 88.07(7); P1−Ni1−S1, 85.69(7); P2−Ni1−S1, 173.39(7);
P1−Ni1−S2, 173.94(8); P2−Ni1−S2, 86.31(7); C27−N1−C28,
113.5(6), C27−N1−C29, 111.3(6); C28−N1−C29, 115.0(6). S4−
Ni2−S3, 100.01(8); P3−Ni2−P4, 88.77(7); P3−Ni2−S3, 85.97(7);
P4−Ni2−S3, 170.30(8); S4−Ni2−P3, 170.71(9); S4−Ni2−P4,
86.28(7); C62−N2−C63, 112.5(6); C62−N2−C64, 114.7(6); C63−
N2−C64, 114.5(6).
the NiS2 and NiP2 planes of 27.6° for the former derivative.
The changes in bond lengths and coordination geometry likely
2−
reflect the weaker donicity of the [adtC6H4Cl
]
ligand.
Containing a more basic diphosphine, NiCl2(dcpe) was
converted to Ni[(SCH2)2NBn](dcpe), albeit in lower yield
than in the dppe case. The 1H and 31P NMR (δ 73.6) and ESI-
MS (m/z 676.3) data confirm formation of the target although
the sample was not obtained in high purity. Nevertheless, the
solid-state structure could be determined by diffraction (Figure
4).
The solid-state structure of Ni[(SCH2)2NBn](dcpe) mirrors
that of the analogous dppe compound. While the Ni−P and
Ni−S bond lengths in the two complexes are virtually identical,
the ligand environment in the dcpe complex is less distorted,
with the NiS2 and NiP2 planes being 2.9° and 10.5° apart in the
two crystallographically independent complexes. This planarity
might result from the greater size and σ-donicity of dcpe versus
dppe. The anion in BnN(CH2SNa)2 was also trapped using
PdCl2(dppe) as the electrophile, affording crystalline Pd-
Figure 3. ORTEP of Ni[(SCH2)2NC6H4Cl](dppe) with ellipsoids
drawn at the 75% probability level. H atoms and a solvent molecule are
omitted for clarity. Selected distances (Å): Ni1−S1, 2.1737(9); Ni1−
S2, 2.1792(10); Ni1−P1, 2.1651(10); Ni1−P2, 2.1663(10). Selected
angles (deg): S1−Ni1−S2, 104.66(4); P1−Ni1−P2, 85.88(4); P1−
Ni1−S1, 156.77(4); P2−Ni1−S1, 87.44(4); P1−Ni1−S2, 89.04(4);
P2−Ni1−S2, 158.65(4); C27−N1−C28, 112.7(3), C27−N1−C29,
118.5 (3); C28−N1−C29, 112.00(2).
1
[(SCH2)2NBn](dppe), whose H NMR spectrum is similar
stereoelectronic effects, this interaction causes the N lone pair
to be directed away from the Ni site.
to that for Ni[(SCH2)2NBn](dppe).
Protonation of Ni[(SCH2)2NBn](dppe). Treatment of
Ni[(SCH2)2NBn](dppe) with HOTf (1 equiv) in CD2Cl2
resulted in protonation, signaled by a change in color from
orange to yellow-orange. The 31P NMR singlet only shifted by
3 ppm downfield upon protonation of the complex, but the 1H
NMR spectrum drastically changed (see Supporting Informa-
tion)a new singlet was observed at δ 8.84, assigned to NH,
and the symmetry of the Ni[(SCH2)2NBn](dppe) is lifted.
Crystallographic analysis of the complex Ni[(SCH2)2-
NC6H4Cl](dppe) again reveals a twisted NiS2P2 core (Figure
3). The average Ni−S (2.179 Å) and Ni−P bond lengths
(2.166 Å) are shortened relative to the benzyl derivative,
highlighting a decrease in electron density at the metal center.
The distortion of the ligand environments with R = 4-ClC6H4
is increased relative to the complex with R = Bn, with a twist of
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While the SCH2N signals appeared as a broad multiplet for the
neutral complex, they appear as doublets-of-triplets for the
ammonium species. Consistent with a Cs-symmetric cation, the
CH2Ph signal remains a doublet after protonation. The
pKaMeCN of the amine was not determined since protonation
labilizes the complex in this solvent. Nonetheless, addition of
be stable. To address this question, the tosylamide
(MeC6H4SO2NR2, abbreviated TsNR2) platform was selected
since such sulfonamides are known to be nonbasic.25 The
targeted TsN(CH2SH)2 was prepared from bis(thioester)
TsN(CH2SAc)2, which in turn was prepared from dichloride
TsN(CH2Cl)2 (Scheme 2). Acid-catalyzed hydrolysis of the
thioester afforded dithiol TsN(CH2SH)2 as analytically pure
+
increasing amounts of BnNH3 (pKaMeCN = 16.76) or Bu3NH+
(pKaMeCN = 18.03) to Ni[(SCH2)2NBn](dppe) shift the 31P
NMR signals toward those of the fully protonated species (see
Supporting Information). The complex Ni[(SCH2)2-
NC6H4Cl)](dppe) did not survive protonation.
1
white crystals, the H NMR spectrum of which is readily
assigned.
Scheme 2. Synthesis of TsN(CH2SH)2 and Its Complexes
Electrochemical Behavior. Cyclic voltammograms (CVs)
of Ni[(SCH2)2NBn](dppe) in CH2Cl2 feature irreversible
oxidations at 0.11 V and a reduction at −2.02 V versus Fc0/+
.
The cathodic wave is shifted to −1.55 V upon addition of 1
equiv of CF3CO2H in CH2Cl2. The anodic shift is attributed to
protonation of the amine and more facile reduction of the
cation [Ni[(SCH2)2N(H)Bn](dppe)]+ relative to its conjugate
base. Anodic shifts of this magnitude are observed for diiron
azadithiolate catalysts.3,23 In the presence of CF3CO2H (1
equiv), no anodic peaks are observed when scanning in the
positive direction. However, once [Ni[(SCH2)2NHBn]-
(dppe)]+ has been reduced, the anodic peak corresponding to
[Ni[(SCH2)2NBn](dppe)]0/+ reappears. These observations
are consistent with the series of electron transfer and chemical
steps in eqs 6−10.
The robustness of TsN(CH2SH)2 is further indicated by its
efficient conversion to dithiolato complexes. Thus, treatment of
the dithiol with Fe3(CO)12 in hot toluene gave
Fe2[(SCH2)2NTs](CO)6, isolated as red crystals. This
synthetic method is analogous to the use of alkyl- and
arylthiols.26 In addition to its characterization by IR and NMR
spectroscopy, Fe2[(SCH2)2NTs](CO)6 was examined by
single-crystal X-ray diffraction (Figure 5). Hexacarbonyl
Fe2[(SCH2)2NTs](CO)6 is structurally similar to many
diiron(I) dithiolates. The Fe centers are within the sum of
their covalent radii (2.64 Å for low-spin Fe) with the Fe−Fe
distance (2.5145(4) Å) being typical for such compounds, for
example, 2.5047(6) Å for Fe2[(SCH2)2NPh](CO)6.14 Like this
MII[(SCH2)2NBn](dppe) + H+
→ [MII[(SCH2)2N(H)Bn](dppe)]+
(6)
[MII[(SCH2)2N(H)Bn](dppe)]+ + e−
→ [MI[(SCH2)2N(H)Bn](dppe)]0
(7)
[MI[(SCH2)2N(H)Bn](dppe)]0 + H+
→ [HMIII[(SCH2)2N(H)Bn](dppe)]+
(8)
[HMIII[(SCH2)2N(H)Bn](dppe)]+
→ [MIII[(SCH2)2NBn](dppe)]+ + H2
(9)
[MIII[(SCH2)2NBn](dppe)]+ + e−
→ [MII[(SCH2)2NBn](dppe)]
(10)
Upon addition of increasing amounts of CF3CO2H to
[Ni[(SCH2)2NHBn](dppe)]+, current increases are observed,
which are attributed to catalytic reduction of the acid to give
H2. The dependence of current on [CF3CO2H] plateaus at 500
mM of acid, which corresponds to a turnover frequency of 22
s−1 according to the usual analysis (see Supporting
Information).24
The CV of Ni[(SCH2)2NC6H4Cl](dppe) in CH2Cl2 features
an irreversible oxidation at 0.22 V and a quasi-reversible
reduction at E1/2 = −1.88 V, both versus Fc0/+. The shifts to
more positive potentials for the cathodic and anodic events for
the ClC6H4 versus Bn derivatives further reflects the influence
of the amine substituent on the metal center, despite its
remoteness.
TsN(CH2SH)2 and Its Fe and Ni Derivatives. The lability
of free azadithiols is proposed to be correlated to the basicity of
the amine group. This hypothesis suggests that free azadithiols
with electron-withdrawing groups on the nitrogen center could
Figure 5. ORTEP of Fe2[(SCH2)2NTs](CO)6 with ellipsoids drawn
at the 50% probability level and H atoms omitted for clarity. Selected
distances (Å): Fe1−Fe2, 2.5145(4); Fe1−S1, 2.2537(5); Fe2−S2,
2.2547(5); Fe2−S1, 2.2619(5); Fe2−S2, 2.2547(5). Selected angles
(deg): Fe1−S1−Fe2, 67.675(15); Fe1−S2−Fe2, 67.718(15); S1−
Fe1−S2, 85.735(17); S1−Fe1−Fe2, 56.318(14); C7−N1−S3,
116.45(14); C7−N1−S3, 119.70(11); C8−N1−S3, 120.63(11).
D
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phenyl analogue, the N center in the Ts derivative is roughly
trigonal planar, the sum of its bond angles being 357°.
Reflecting the nonbasic nature of this tosylamido center, a
solution of the diiron complex was found to be unaffected by
HBF4. The nonbasicity of Fe2[(SCH2)2NTs](CO)6 is in
contrast to the easy protonation of other azadithiolato
complexes with R = alkyl or aryl.3
In the presence of base, TsN(CH2SH)2 was also found to
react with NiCl2(dppe) to give Ni[(SCH2)2NTs](dppe),
isolated as air-stable red crystals. The structure of this Ni
complex was verified by X-ray diffraction (Figure 6).
withdrawing, the corresponding dithiolates appear more stable.
This effect is indicated by the improved yields of Ni[(SCH2)2-
NC6H4Cl](dppe) relative to the N-benzyl derivative. More
dramatically, N-substitution with p-toluenesulfonyl (Ts)
allowed full characterization of the dithiol TsN(CH2SH)2.
This dithiol was shown to react efficiently with iron carbonyls
to give the corresponding azadithiolatodiiron(I) complex. In
this complex, however, the nitrogen center is insufficiently basic
to sustain protonation. In terms of their ease of synthesis and
low basicity, the [adtTs]2− derivatives resemble analogous N-
acetylated ligands [adtAc]2−.29
2. Azadithiolate is Stabilized by Coordination, Even to
One Metal. Although hundreds of [adtR]2− complexes have
been reported, few are not components of a diiron complex. In
this paper, the N-substituted [adtR]2− ligands were stabilized
through formation of complexes of the familiar Ni(dithiolate)-
(dppe) motif.30 Aside from the nickel complexes reported in
this paper, the titanocene derivatives (C5H4R)2Ti(adtR)
(prepared from (C5H4R′)2Ti(SH)2 and (CH2NR)3; R′ = H,
Me; R = Ph, Me) feature nonbridging [adtR]2− complexes.15
Finally, these results have some bearing on the biosynthesis
of [FeFe] hydrogenase. Containing three unusual cofactors,
CO, CN−, and [adtH]2−, as well as the attached 4Fe−4S cluster,
the active site is assembled following a multistep maturation
pathway.10,31 The source of CO and CN− has been elucidated,
but the origin of [adtH]2− remains unsolved. As demonstrated
here, the cofactor in its various protonated forms
[HnadtH](2−n)− is expected to be too unstable to persist in the
absence of metal ions. Indeed, the biochemical evidence32 and
some literature precedents33 suggest that the azadithiolate is
biosynthesized on an Fe-containing scaffold.
Figure 6. ORTEP of Ni[(SCH2)2NTs](dppe) with ellipsoids drawn at
the 50% probability level. H atoms and disorder are omitted for clarity.
Selected distances (Å): Ni1−S1, 2.1943(5); N1−S2, 2.1963(5); Ni1−
P1, 2.1804(5); Ni1−P2, 2.1873(5). Selected angles (deg): S1−Ni1−
S2, 94.568(19); P1−Ni1−P2, 87.143(18); P1−Ni1−S1, 90.505(18);
P2−Ni1−S1, 168.68(2); P1−Ni1−S2, 173.82(2); P2−Ni1−S2,
88.549(18); C27−N1−C28, 116.95(15), C27−N1−S3, 119.69(13);
C28−N1−S3, 117.26(13).
EXPERIMENTAL SECTION
■
General Considerations. Unless otherwise stated, reactions were
conducted using standard Schlenk techniques, and all reagents were
purchased from Sigma-Aldrich or Fisher. Unless otherwise noted, all
solvents were HPLC grade and purified using an alumina filtration
system (Glass Contour, Irvine, CA). ESI-MS data were acquired using
a Waters Micromass Quattro II or ZMD spectrometer with analytes in
dilute CH2Cl2 solution. Analytical data were acquired using an Exeter
Analytical CE-440 elemental analyzer. NMR data were acquired using
Varian U400, U500, and VXR500 spectrometers. Chemical shifts (in
The complex Ni[(SCH2)2NTs](dppe) was found to be
virtually isostructural to its NBn congener, however, with less
distortion of the Ni center (the NiS2 and NiP2 interplanar angle
being 11.7°). As with the diiron complex, the N atom is
approximately planar (angle sum = 354°), but the Ni complex
differs in that the sp2-hybridization causes puckering of the
chelate ring, in contrast to the idealized chair/boat con-
formation in Fe2[(SCH2)2NTs](CO)6.
1
parts per million) were referenced to residual solvent peaks (for H,
13C) or external 85% H3PO4 (for 31P). Solution IR spectra were
recorded on a PerkinElmer Spectrum 100 FTIR spectrometer.
Crystallographic data were collected using a Siemens SMART
diffractometer equipped with a Mo Kα source (λ = 0.710 73 Å) and
an Apex II detector.
CONCLUSIONS
■
The present work was motivated by the recent confirmation of
the azadithiolate ([adtH]2−) cofactor in the [FeFe] hydro-
genases.11 Our studies were intended to probe the stability of
the free azadithiol and its salts. A simplifying aspect of our
endeavor was the use of the N-substituted analogues of
[adtH]2− rather than the secondary amine itself. This
compromise was necessary because the precursor HN-
(CH2SAc)2 is unknown, and a synthesis of this compound
could not be devised. The work described here led us to two
instructive conclusions.
BnN(CH2SAc)2. In a modification of the method of Izawa,20
a
solution of benzylamine (10.72 g, 100 mmol) in 100 mL of 95% EtOH
was treated with formaldehyde (37% in MeOH/H2O, 24 mL). The
mixture was heated at 60 °C for 30 min and then treated with AcSH
(14.1 mL, 200 mmol). After 2 h, the reaction mixture was cooled to
−17 °C, when colorless crystals formed. The crystals were isolated by
filtration, washed with cold 95% EtOH, and dried briefly under
vacuum. Yield: 22.52 g (79%). 1H NMR (400 MHz, deuterated
dimethyl sulfoxide (DMSO-d6), 298 K): δ 7.34−7.23 (m, 5H, C6H5),
4.51 (s, 4H, C(O)CH2), 3.61 (s, 2H, PhCH2), 2.35 (s, 6H, CH3). 13
C
1. Azadithiolate Salts and Azadithiols Are Labile. The
instability is associated with the proximity of the basic nitrogen
centers to the thiol groups, this labile motif also being present
in the yet-to-be-isolated thioaminals (R2NCH2SH). In contrast,
related compounds are stable when SH is replaced by S-
alkyl27,28 or when the spacer between the thiol and the amine is
extended, as is the case for cysteamine derivatives
(R2NCH2CH2SH).27 When the N-substituent is electron-
NMR (75 MHz, DMSO-d6, 298 K): δ 196 (CO), 137 (Ph−C1),
129 (PhC2, PhC2′), 128 (PhC2, PhC2′), 128 (Ph−C1), 56.4 (C(O)−
CH2), 53.6 (PhCH2), 31.5 (CH3). Anal. Calcd for C13H17NO2S2: C,
55.09; H, 6.05; N, 4.94. Found: C, 55.24; H, 6.02; N, 4.98%.
Hydrolysis of BnN(CH2SAc)2. A solution of BnN(CH2SAc)2
(0.58 g, 2.00 mmol) in 10 mL of EtOH was treated with a 2 M
solution of HCl in Et2O (4.00 mL, 8.00 mmol) under Ar. After the
mixture was stirred for 15 h, the white precipitate was isolated by
E
DOI: 10.1021/acs.inorgchem.5b00290
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
filtration in air and washed with 2 × 5 mL of EtOH, yielding 0.370 g of
crude product. 1H NMR analysis (1,3,5-C6H3(OMe)3 integration
standard) of the precipitate showed 63% [BnNCH2SCH2]2, indicating
a yield of 0.23 g of [BnNCH2SCH2]2 (theoretical yield: 330 mg). The
reaction of BnN(CH2SAc)2 with NaOMe afforded the known
compound BnN(CH2OMe)2.34
m/z 702.1 (MH+). Anal. Calcd for C35H35NP2Pd2S2: C, 59.87; H,
5.02; N, 1.99. Found: C, 59.55; H, 5.12; N, 1.64%.
ClC6H4N(CH2SAc)2. A solution of 4-chloroaniline (12.76 g, 100
mmol) in 100 mL of 95% EtOH was treated with formaldehyde (37%
in methanol/H2O, 24 mL). The mixture was heated at 60 °C for 30
min and then treated with AcSH (14.1 mL, 200 mmol). After 2 h, the
reaction mixture was poured into ∼100 mL of ice−water, when yellow
crystals formed. The crystals were collected by filtration and washed
with 100 mL of cold EtOH. Yield: 24.6 g (81%). 1H NMR (500 MHz,
DMSO-d6, 298 K): δ 7.29 (d, 3JHH = 7.69 Hz, 2H, C6H4), 6.80 (d, 3JHH
[BnNCH2SCH2]2. The following is an adaptation of a method for
the α-methylbenzylamine derivative.35 A solution of benzylamine (4.9
g, 0.045 mol) in 90 mL of MeOH was added to cold 37% aqueous
formaldehyde (27 mL, 0.352 mol) at 0 °C. After it was stirred for 5
min at 0 °C, the solution was treated with a solution of NaSH·xH2O
(13.53 g, 0.12 mol) in 115 mL of MeOH. After it was stirred for 5 min
at 0 °C for 24 h, the cloudy solution was concentrated to half its
volume under vacuum causing an oil to precipitate. Approximately 30
mL of the oil was separated from the reaction mixture. The oil was
mixed with 30 mL of acetone and diluted with 60 mL of EtOH. The
solution was concentrated under vacuum until white crystals formed.
The crystals were isolated by filtration and washed with 2 × 20 mL of
EtOH. Yield: (0.560 g, 18%). 1H NMR (500 MHz, DMSO-d6) δ
7.24−7.34 (m, J = 15.8, 7.4 Hz, 10H), 4.54/4.51/4.38/4.35 (ABq,
8H), 3.87 (s, 4H). These data match those from samples prepared
according to literature methods.23,24 Anal. Calcd for C18H22N2S2: C,
65.41; H, 6.71; N, 8.48. Found: C, 65.18; H, 6.66; N, 8.43%. ESI-MS
(m/z): 331 (MH+).
= 7.69 Hz, 2H, C6H4), 5.10 (s, 4H, C(O)CH2), 2.35 (s, 6H, CH3). 13
C
NMR (75.47 MHz, DMSO-d6, 298 K): δ 196 (CO), 143 (C6H4),
129 (C6H4), 124 (C6H4), 116 (C6H4), 52.1 (C(O)CH2), 31.2 (CH3).
Anal. Calcd for C12H14ClNO2S2: C, 47.44; H, 4.64; N, 4.61. Found: C,
47.13; H, 4.5; N, 4.61%. Also prepared analogously was 4-
MeC6H4N(CH2SAc)2. Anal. Calcd for C13H17NO2S2: C, 55.09; H,
6.05; N, 4.94. Found: C, 55.24; H, 6.02; N, 4.98%.
Ni[(SCH2)2NC6H4Cl](dppe). A slurry was prepared of ClC6H4N-
(CH2SAc)2 (304.8 mg, 1.00 mmol), NaOtBu (192.2 mg, 2.00 mmol),
and NiCl2(dppe) (528.0 mg, 1.00 mmol) in THF (45 mL) at −78 °C
with stirring. After 4 h, the purple-red mixture was allowed to warm to
room temperature, resulting in a red solution and some green solid
precipitate. The solids were removed by filtration and carefully layered
1
with pentane, affording red-orange crystals. Yield: 505 mg (75%). H
Ni[(SCH2)2NBn](dppe). A slurry was prepared of BnN(CH2SAc)2
(283.4 mg, 1.00 mmol), NaOtBu (192.2 mg, 2.00 mmol), and
NiCl2(dppe) (528.0 mg, 1.00 mmol) in THF (45 mL) at −78 °C with
stirring. After 4 h, the purple-red mixture was allowed to warm to
room temperature and filtered, with the filtrate being carefully layered
with pentane. Red-orange crystals of the product were carefully
isolated using a pipet, the remainder of the material (an orange
powder) being recrystallized from CH2Cl2/pentane. The combined
crops were washed with pentane (2 × 10 mL) and dried to afford the
title compound as red-orange crystals. Yield: 210 mg (32%). 1H NMR
(500 MHz, CD2Cl2, 298 K): δ 7.89 (m, 8H, H2), 7.53 (m, 4H, H4),
7.49 (m, 8H, H3), 7.33 (d, 3JHH = 7.5 Hz, 2H, H2-CH2Ph), 7.24 (dd,
3JHH = 7.5 Hz, 3JHH = 7.5 Hz, 2H, H3-CH2Ph), 7.19 (d, 3JHH = 7.5 Hz,
NMR (500 MHz, CD2Cl2, 298 K): δ 7.89 (m, 8H, H2), 7.53 (m, 4H,
H4), 7.49 (m, 8H, H3), 7.33 (d, 3JHH = 7.5 Hz, 2H, H2-CH2Ph), 7.24
(dd, 3JHH = 7.5 Hz, 3JHH = 7.5 Hz, 2H, H3-CH2Ph), 7.19 (d, 3JHH = 7.5
Hz, 1H, H4-CH2Ph), 3.99 (s, 2H, CH2Ph), 3.90 (d, 4JPH = 4.3 Hz, 4H,
3
SCH2), 2.18 (d, JPH = 16.9 Hz, 4H, PCH2) (NMR analysis of the
green solid was the same, except for the presence of THF). 31P{1H}
NMR (202 MHz, CD2Cl2, 298 K): δ 57.3. ESI-MS: m/z 654.1 (MH+).
Red prisms of Ni[(SCH2)2NBn](dppe) formed upon slow diffusion of
pentane layered onto a concentrated CH2Cl2 solution of the title
compound at −28 °C. Anal. Calcd for C34H32ClNNiP2S2·CH2Cl2: C,
55.33; H, 4.51; N, 1.84. Found: C, 55.72; H, 4.35; N, 2.08%.
TsN(CH2SAc)2. A suspension of KSAc (2.73 g, 23.9 mmol) and
TsN(CH2Cl)236 (3.06 g, 11.4 mmol) in THF (60 mL) was stirred for
27 h, after which the reaction mixture was filtered to remove NaCl and
the colorless filtrate was evaporated to afford a yellow oily residue. A
CH2Cl2 extract of the crude product was chromatographed on silica
gel eluting with 4:1 hexane/EtOAc. The second band was collected,
and the solvent was removed to yield the product TsN(CH2SAc)2 as
4
1H, H4-CH2Ph), 3.99 (s, 2H, CH2Ph), 3.90 (d, JPH = 4.3 Hz, 4H,
3
SCH2), 2.18 (d, JPH = 16.9 Hz, 4H, PCH2). 31P{1H} NMR (202
MHz, CD2Cl2, 298 K): δ 57.3. ESI-MS: m/z 654.1 (MH+). Red prisms
of Ni[(SCH2)2NBn](dppe) formed upon slow diffusion of pentane
layered onto a concentrated CH2Cl2 solution of the title compound at
−28 °C.
1
colorless crystals. Yield: 3.04 g (77%). H NMR (400 MHz, CDCl3,
Protonation of Ni[(SCH2)2NBn](dppe). A solution of Ni-
[(SCH2)2NBn](dppe) (5.4 mg, 8.25 μmol) in 0.5 mL of CD2Cl2 in
a J-young tube was treated with HOTf (8.4 μL, 1 M) resulting in a
color from orange to yellow-orange. 1H NMR (500 MHz, CD2Cl2): δ
293 K): δ 7.69 (d, 2H, H2), 7.32 (d, 2H, H3), 4.89 (s, 4H, NCH2S),
2.45 (s, 3H, CH3), 2.31 (s, 6H, C(O)CH3). Anal. Calcd for
C13H17NO4S3: C, 44.94; H, 4.93; N, 4.03. Found: C, 45.17; H, 4.76,
N, 4.32%.
8.84 (br. s, 1H, N(H)Bn), 7.80−7.36 (m, 20 H, PPh2), 4.19 (dt, 3JHH
=
12.4, 4.0 Hz, 2H, SCH2N), 3.79 (dt, 3JHH = 12.4, 4.2 Hz, 2H, SCH2N).
TsN(CH2SH)2. A solution of HCl (12 M aqueous, 4.88 mL, 5.76
mmol) in MeOH (100 mL) was sparged with N2 and then added to a
solution of TsN(CH2SAc)2 (0.993 g, 2.86 mmol) in MeOH (20 mL).
The resulting homogeneous solution was stirred for 21 h at 50 °C,
after which solvent evaporation afforded a white residue. A CH2Cl2
extract of this solid was chromatographed (SiO2, CH2Cl2 eluent). The
first band was collected and evaporated to dryness to give the dithiol as
a white solid. Yield: 310 mg (41%). 1H NMR (400 MHz, CDCl3, 293
K): δ 7.72 (d, 2H, H2), 7.34 (d, 2H, H3), 4.66 (d, 4H, NCH2S), 2.44
(s, 3H, CH3), 1.79 (t, 2H, SH). Anal. Calcd for C9H13NO2S3: C,
41.04; H, 4.97; N, 5.32. Found: C, 41.31; H, 4.99; N, 5.19%. mp 51−
53 °C.
Fe2[(SCH2)2NTs](CO)6. A solution of TsN(CH2SH)2 (263.4 mg,
1.00 mmol) and Fe3(CO)12 (514.1 mg, 1.02 mmol) in toluene (30
mL) was stirred at 90 °C for 3 h, during which time the solution
assumed a red color. The reaction mixture was evaporated to yield 472
mg of brick-red solid, which crystallized from CH2Cl2 (5 mL) upon
the addition of hexanes followed by cooling. Yield: 189 mg (35%). 1H
NMR (400 MHz, CDCl3, 293 K): δ 7.50 (d, 2H), 7.30 (d, 2H), 3.65
(s, 4H), 2.43 (s, 3H). FTIR (CH2Cl2): νCO 2080, 2043, 2005, 1985
cm−1. Anal. Calcd for C15H11Fe2NO8S3: C, 33.29; H, 2.05; N, 2.59.
Found: C, 33.10; H, 1.85; N, 2.63%. Red prisms of Fe2[(SCH2)2NTs]-
3
3
(ddt, JPH = 14.3 Hz, JHH = 7.9, 3.7 Hz, 4H, PCH2). 31P{1H} NMR
(202 MHz, CD2Cl2, 298 K): δ 61.03.
Ni[(SCH2)2NBn](dcpe). This compound was prepared as yellow-
orange crystals analogously to Ni[(SCH2)2NBn](dppe), using
NiCl2(dcpe) as the precursor. Yield: 28%. 1H NMR (500 MHz,
CD2Cl2, 298 K): δ 7.42−7.18 (m, 5H, Ph), 3.95 (s, 2H, CH2Ph), 3.89
(d, 4JPH = 3.0 Hz, 4H, SCH2), 2.58 (d, 3JPH = 12.7 Hz, 2H, PCH), 2.37
3
3
(d, JPH = 12.7 Hz, 4H, PCH2), 2.28 (d, JPH = 13.8 Hz, 2H, PCH),
2.20−1.46 (m, 40H, (CH2)5). 31P NMR (202 MHz, CD2Cl2, 298 K):
δ 73.6. ESI-MS: m/z 676.3 (MH+). Orange blocks of Ni[(SCH2)2-
NBn](dcpe)·CH2Cl2 formed upon slow diffusion of pentane layered
onto a concentrated CH2Cl2 solution of the title compound at −28
°C.
Pd[(SCH2)2NBn](dppe). This compound was prepared as orange
crystals analogously to Ni[(SCH2)2NBn](dppe), using PdCl2(dppe)
as the precursor. Yield: 24%. 1H NMR (500 MHz, CD2Cl2, 298 K): δ
7.82 (m, 8H, H2), 7.52 (m, 4H, H4), 7.48 (m, 8H, H3), 7.35 (d, 3JHH
= 7.6 Hz, 2H, H2-CH2Ph), 7.24 (dd, 3JHH = 7.9 Hz, 3JHH = 7.9 Hz, 2H,
H3-CH2Ph), 7.18 (m, 1H, H4-CH2Ph), 4.19 (s, 2H, CH2S), 4.19 (s,
2H, CH2S), 4.17 (s, 2H, CH2Ph), 2.41 (s, 2H, PCH2), 2.37 (s, 2H,
PCH2). 31P{1H} NMR (202 MHz, CD2Cl2, 298 K): δ 50.3. ESI-MS:
F
DOI: 10.1021/acs.inorgchem.5b00290
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
(CO)6 formed upon slow diffusion of hexane layered onto a
concentrated CH2Cl2 solution of the title compound.
(9) Stich, T. A.; Myers, W. K.; Britt, R. D. Acc. Chem. Res. 2014, 47,
2235−2243.
Ni[(SCH2)2NTs](dppe). A solution of TsN(CH2SH)2 (1.57 g, 6.98
mmol) in 100 mL of CH2Cl2 was added to a slurry of NiCl2(dppe)
(2.63 g, 5.00 mmol) and 150 mL of CH2Cl2. A solution of NaOEt
(0.68 g, 10.0 mmol) in 45 mL of EtOH was added into the mixture.
The mixture darkened in color, the NiCl2(dppe) dissolved, and NaCl
precipitated. After the reaction mixture was stirred for 3 h, solvent was
removed under vacuum. The product was extracted into CH2Cl2 (90
mL). The extract was concentrated to a volume of 10 mL. Brick-red
powder precipitated from the concentrate upon the addition of 90 mL
of hexane. Yield: 3.15 g (88%). 1H NMR (500 MHz, CD2Cl2, 293 K):
δ 7.74 (dd, 8H, Ph), 7.63 (d, 2H, Ts), 7.52 (t, 4H, Ph), 7.46 (t, 8H,
Ph), 7.21 (d, 2H, Ts), 4.21 (d, 4H, NCH2S), 2.38 (s, 3H, CH3), 2.19
(d, 4H, PCH2). 13C{1H} NMR (125 MHz, CD2Cl2, 293 K): δ 143.2,
134, 132, 130, 129, 128, 125, 121, 43.7, 27.5, 21.6. 31P{1H} NMR (202
MHz, CD2Cl2, 293 K): δ 57.6. Anal. Calcd for C35H35NNiO2P2S3: C,
58.51; H, 4.91; N, 1.95. Found: C, 57.88; H, 4.74; N, 2.06%. Red
prisms of Ni[(SCH2)2NTs](dppe) formed upon slow diffusion of
hexane layered onto a concentrated CH2Cl2 solution of the title
compound.
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ASSOCIATED CONTENT
* Supporting Information
■
Schollhammer, P.; Talarmin, J.; Muir, K. W. Inorg. Chem. 2004, 43,
8203−8205.
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NMR, ESI-MS, and IR spectra, crystallographic data and
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[Ni[(SCH2)2NHBn](dppe)]+ (1 mM) versus [CF3CO2H]
added, where ip is the current with 1 mM acid. The Supporting
Information is available free of charge on the ACS Publications
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AUTHOR INFORMATION
Corresponding Author
*E-mail: rauchfuz@illinois.edu.
■
Blake, A. J.; Cooke, P. A.; Wilson, C.; Schroder, M. Proc. Natl. Acad.
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Present Address
†Department of Chemistry, Indian Institute of Technology
Kanpur, Kanpur 208016, India.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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This project was supported by the National Institutes of Health
(No. GM061153). R.A. is grateful for the Rubicon grant from
The Netherlands Organisation for Scientific Research (NWO).
We thank Drs. A. Fuller and C. Richers for advice and
assistance.
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