Hydrogen-bonding thiourea organocatalysts: The privileged 3,5-bis(trifluoromethyl)phenyl group

Article abstract of DOI:10.1002/ejoc.201200739

We present evidence that the privileged use of the 3,5-bis(trifluoromethyl) phenyl group in thiourea organocatalysis is due to the involvement of the ortho-CH bond in the binding event with Lewis-basic sites. We utilized a combination of low-temperature IR spectroscopy, 2D NMR spectroscopy, nano-MS (ESI) investigations, as well as density functional theory computations [M06/6-31+G(d,p), including solvent corrections as well as natural bond orbital and atoms-in-molecules analyses] to support our conclusions that bear implications for catalyst design. The present work reveals that thiourea derivatives bearing a 3,5-bis(trifluoromethyl)phenyl group interact with Lewis basic sites of carbonyl derivatives through NH and highly polarized ortho-CH interactions in hydrogen-bonded complexes. Evidence is provided through a combination of DFT, variable-temperature IR and NMR spectroscopy, as well as MS (ESI) studies.

Full text of DOI:10.1002/ejoc.201200739

Job/Unit: O20739
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Date: 10-09-12 16:13:18
Pages: 10
FULL PAPER
DOI: 10.1002/ejoc.201200739
Hydrogen-Bonding Thiourea Organocatalysts: The Privileged
3,5-Bis(trifluoromethyl)phenyl Group
Katharina M. Lippert,[a] Kira Hof,[a] Dennis Gerbig,[a] David Ley,[a] Heike Hausmann,[a]
Sabine Guenther,[b] and Peter R. Schreiner*[a]
Keywords: Density functional theory computations / IR spectroscopy / NMR spectroscopy / Organocatalysis / Thiourea
derivatives
We present evidence that the privileged use of the 3,5-bis(tri-
fluoromethyl)phenyl group in thiourea organocatalysis is due
to the involvement of the ortho-CH bond in the binding event
with Lewis-basic sites. We utilized a combination of low-tem-
perature IR spectroscopy, 2D NMR spectroscopy, nano-MS
(ESI) investigations, as well as density functional theory com-
putations [M06/6-31+G(d,p), including solvent corrections as
well as natural bond orbital and atoms-in-molecules analy-
ses] to support our conclusions that bear implications for cat-
alyst design.
Introduction
rived catalysts (Figure 1).[4] It appears that the 3,5-bis(tri-
Urea and thiourea derivatives are popular hydrogen-bond- fluoromethyl)phenyl moiety generally has beneficial effects
ing catalysts that have been utilized successfully in a large on organocatalysts. This may inter alia involve an increase
variety of organocatalytic transformations.[1] Many cata- in catalyst polarity, polarizability, acidity,[5] and π–π inter-
lysts display the 3,5-bis(trifluoromethyl)phenyl group[2] that actions[2k,6] through the highly polarized aryl groups. Here
was first introduced as a key structural motif in thiourea we describe that the involvement of the highly polar ortho-
catalysis in 2002.[3] Remarkably, this moiety is also present CH bond is also quite important for catalyst–substrate in-
in some of the most active proline and phosphoric acid de- teractions in the case of thiourea catalysis.[2k,7] Evidence for
Figure 1. Selection of catalysts bearing a 3,5-bis(trifluoromethyl)phenyl group.
the non-negligible role of CH–heteroatom interactions
[a] Institute of Organic Chemistry, Justus-Liebig University,
comes from early IR and NMR spectroscopic studies.[8]
Heinrich-Buff-Ring 58, 35392 Giessen, Germany
Fax: +49-641-99-34309
Such interactions increase with increasing carbon s-content
in the hybridization and in the presence of electron-with-
drawing groups.[8,9] Hydrogen-bonding interactions of polar
aromatic CH bonds with Lewis basic sites have been well
studied but,[9,10] to the best of our knowledge, not in the
context of hydrogen-bonding organocatalysis.
E-mail: prs@org.chemie.uni-giessen.de
Homepage: http://www.chemie.uni-giessen.de/schreiner
[b] Institute of Inorganic and Analytical Chemistry, Justus-Liebig
University,
Schubertstr. 60, Bldg.16, 35392 Giessen, Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200739.
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Individual Components
Results and Discussion
In the absence of a Lewis basic donor, structure 2, which
has not been employed as a catalyst, displays two conform-
ers with E,Z- (2_E,Z) and Z,Z-orientations (2_Z,Z) of the
N–H bonds (Figure 3), with the 2_E,Z form being slightly
more stable as derived from computations and its crystal
structure. However, our NMR spectroscopic studies imply
that in [D8]toluene at room temperature, conformer 2_Z,Z
is preferred, whereas 2_Z,E predominates at temperatures
below 200 K; that is, the rotation around the C–N bonds is
facile (cf. Supporting Information, Figure S29).
We utilized low-temperature NMR and IR techniques as
well as modern density functional theory (DFT) computa-
tions[11] to corroborate our findings. While there are numer-
ous complexes of anions and neutrals with (thio)urea deriv-
atives, we are unaware of reports on the involvement of C–
H bonding in the binding event.[1g,12] A pertinent example
in the context of thiourea binding to neutrals comes from
the work of Waymouth and Hedrick, who examined effects
of supramolecular recognition for living polymerization of
lactide by utilizing catalysts bearing the 3,5-bis(trifluorome-
thyl)phenyl motif.[7d,13] To elucidate the structural changes
upon binding between catalyst and substrate, we examined
the interactions of thiourea derivatives 1–4 with neutrals 5–
9 (Figure 2).
Figure 3. The lowest-lying conformers of 1, 2, and 5 computed at
M06/6-31+G(d,p) at 0 K. Compounds 1_Cs and 2_E,Z are also
present in the crystal structure.
Catalyst 1 prefers a Z,Z-orientation of the N–H protons
(Figure 3) in solution, in the crystal, and computationally.
At temperatures below 190 K in [D8]THF, 1 transforms into
the Z,E-conformation, as evident from the separated signals
1
Figure 2. Investigated thiourea derivatives and substrates 5–9.
of the N–H protons (Figure 4). A H–15N HSQC spectrum
1
Figure 4. Stacked H NMR (600 MHz) spectra of 1 (0.01 mmol, 13.3 mm) in [D8]THF.
2
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Hydrogen-Bonding Thiourea Organocatalysts
Figure 5. (a)–(c) Selected ranges of the IR spectra in [D8]toluene; temperatures are given above each IR spectrum. (a) 5 (10 mm); (b) 2
(10 mm) and 5 (10 mm); (c) 1 (10 mm) and 5 (10 mm). (d) Lowest-lying complex of 2·5. (e) Lowest-lying complex of 1·5. Both complexes
were computed at the M06/6-31+G(d,p) level of theory. Dissociation energies (D298) given in kcalmol–1. Values in parentheses were
computed with the PCM model for toluene employing UAHF radii.
at 183 K clearly identifies two species with different N–H variable-temperature IR spectra (Figure 5b). M06/6-
proton shifts (cf. Supporting Information, Figure S8). 31+G(d,p) computations in the gas phase and in solution
Again, C–N bond rotation is facile.
at room temperature give negative dissociation energies so
The half-chair (i.e., 5_hc) conformer of uncomplexed that complex formation of 2·5 seems rather unlikely. On the
lactone 5 is preferred computationally by 1.1 kcalmol–1 contrary, the corresponding NMR spectra for 1 show large
over the boat conformer (5_b, Figure 3). IR measurements changes in the chemical shifts (Δδ ≈ 1.8 ppm) for the NH
in [D8]toluene at room temperature show a broad C=O protons (Figure 6c,d) but also for the ortho-protons (Δδ ≈
band wh a shoulder (Figure 5a, at 1745 cm–1) implying a 0.7 ppm). The same applies to the 13C NMR absorptions
mixture of 5_hc and 5_b. At low temperatures, the concen- (Figure 7) of the carbonyl (Δδ ≈ 3.2 ppm) and methylene
tration of 5_hc increases, as evidenced from the growing carbon atoms next to the ring oxygen (Δδ ≈ 1.4 ppm).[7d]
band at 1733 cm–1.
The NOESY (Figure 8b), 19F–1H HOESY (Figure 9), and
IR spectra equally indicate 1·5 complex formation. The ob-
served 19F coupling with the hydrogen atoms of the methyl-
ene group next to the ring oxygen clearly indicate a very
close spatial relationship between the ortho-C–H and the
ring oxygen. The IR spectra of a 1:1 mixture of 1 and 5 in
[D8]toluene reveal a band at 1744 cm–1 originating from free
5 and a redshifted band at 1712 cm–1, indicating a hydro-
gen-bonded complex of 1·5 (Figure 5c). These findings are
also supported by MS (ESI) measurements (cf. Supporting
Information) where the mass of [1·5+H]+ = 601.08 was
identified. M06/6-31G+(d,p) computations (Figure 5e) in
Complexation Studies
Turning to mixtures of the thiourea derivatives and the
Lewis basic substrates we find that the H NMR and 13C
1
NMR spectra of 2 in [D8]toluene at room temperature in
the absence and presence of 5 are rather similar (Fig-
ure 6a,b; 13C NMR spectra are depicted in Figure 7) indi-
cating that a complex does not form under these conditions.
This is also supported by the absence of NOE cross peaks
(Figure 8a) and the virtually unchanged (relative to free 5)
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Figure 6. Sections of the 1H NMR spectra in [D8]toluene at 298 K. (a) Free 2 (13.3 mm); (b) complex 2·5 (2, 13.3 mm; 5, 13.3 mm); (c) free
1 (13.3 mm); (d) complex 1·5 (1, 13.3 mm; 5, 13.3 mm).
Figure 7. Sections of the 13C NMR spectra in [D8]toluene at 298 K. (a) Free 5 (13.3 mm); (b) complex 2·5 (2, 13.3 mm; 5, 13.3 mm);
(c) complex 1·5 (1, 13.3 mm; 5, 13.3 mm).
the gas phase give D298 = 1.8 kcalmol–1 (in solution D298
=
orbital being energetically ≈2.5-fold weaker than the N–H···
–2.5 kcalmol–1) so that complex formation of 1·5 is pre- O=C interaction. This is confirmed through a quantum
ferred at room temperature, with 1 binding through double theory of atoms in molecules (QTAIM)[14] study by utilizing
hydrogen bonding to the C=O group and the ortho-proton AIMAll:[15] an analysis of the electron density reveals bond
binding to the ring oxygen.
critical points (BCPs) for the interactions noted above. In
Natural bond order (NBO) analysis confirmed the N–H··· particular, we found a BCP for a hydrogen bond between
O=C as well as the C–H···Oring interactions in 1·5, with the the ring oxygen and the ortho-proton of ρ ≈ 1.20ϫ10–2 au,
C–H···Oring oxygen lone pair interaction with the C–H σ* which is in the range of weak hydrogen bonds; there is also
4
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Hydrogen-Bonding Thiourea Organocatalysts
Figure 8. Sections of the NOESY spectra of 1:1 mixtures of thiourea derivatives and 5 in [D8]toluene at 298 K. (a) 2 (13.3 mm) and 5
(13.3 mm); (b) 1 (13.3 mm) and 5 (13.3 mm). Expected and observed NOE signals are highlighted with a blue frame.
tively correlates with these pKa values, the chemical shift
differences (Δδ) may be suggestive of the potential activity
of a particular catalyst. This correlation is evident from the
presence of acidifying CF3 groups, for which the pKa values
and Δδ differences follow the order 1 Ͼ 3 Ͼ 4 Ͼ 2.[5b]
Next we investigated the complexation of 1 with 6–9. Al-
though 6 bears no ring oxygen as an additional hydrogen-
bonding contact point, we identified an NH···O=C hydro-
gen-bonded complex through NOESY as well as IR mea-
surements and DFT computations (Figure 10 and the Sup-
porting Information). Both NH- and the ortho-protons of
1 bind to the carbonyl oxygen of 6, because we find cross-
peaks between the α-protons of 6 with the NH proton as
well as with the ortho-proton. Computing the NBOs we
found no C–H···O interaction, but this should be a conse-
quence of long distance between the ortho-proton and the
Figure 9. Section of the 19F–1H HOESY spectrum of a 1:1 mixture
of 1 and 5 in [D8]toluene at 298 K showing the cross peak between
the fluorine of the CF3 group and the methylene group protons
C=O group and according to that no correlation between
the oxygen and C–H σ* orbital was visible; there is no C–
H···O BCP.[17] Carbonyl derivatives bearing two C=O
groups and a ring oxygen (i.e., 7 and 8) lead to complexes
as identified by IR and MS (ESI) techniques (Figure 10).
The ring C=O IR redshift implies a hydrogen-bonded com-
plex with the oxazolidinone ring. The NH and the ortho-
protons of 1 bind to the ring C=O group of 7 and 8, respec-
tively. Computations reveal interactions of the ortho-pro-
tons with the ring oxygen for 1·7 and 1·8. Without the ring
oxygen structure 9 binds to 1 through the crotonyl C=O
group (Figure 10). Complex 1·9 was found by NMR and
IR spectroscopy and MS (ESI) measurements as well as
DFT computations.
adjacent to the ring oxygen; 1 (13.3 mm) and 5 (13.3 mm).
a BCP between the fluorine and the methylene proton adja-
cent to the ring oxygen.[14]
Thiourea derivatives 3 and 4 also bind to 5, but the IR
spectra (at the same concentrations, cf. Supporting Infor-
mation) show that the amounts of complexes 3·5 and 4·5
are much lower than for 1·5. NMR cross-peaks were only
observed for 3·5, and it can equilibrate between two low-
energetically lying complexes (cf. Supporting Information).
NBO analysis revealed both C–H···Oring interactions
through the ortho- or cyclohexyl methylene protons with
the ring oxygen owing to an interaction of the ring oxygen’s
lone pair with the C–H σ* orbital (cf. Supporting Infor-
In the last years, many catalysts bearing the 3,5-bis(tri-
mation, Figure S52 and Figure 10), similar to that found fluoromethyl)phenyl moiety were reported and used in vari-
for 1·5 but weaker.[16] The hydrogen bonding in 3·5 is also ous hydrogen-bond-assisted organocatalytic reactions.[18]
evident from the downfield shifts of the NH- and ortho- Many provide high enantioselectivities and high yields.
protons. These downfield shifts correlate well with the thio- Nevertheless, reactions for some systems fail due to a lack
urea NH acidities,[5b] and as catalytic acidity also qualita- of substrate-specific interactions with the catalyst and show
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Figure 10. Complexes as identified by the indicated methods through NMR and IR spectroscopy and/or MS (ESI). Possible hydrogen
bonds (dashed lines) where drawn for each complex demonstrated by relevant shortened distances between thiourea and carbonyl deriva-
tive by comparing NMR and computational results.
deuterated chemicals {[D8]THF, [D8]toluene (99.8%, purchased
from Deutero GmbH or euroisotop GmbH)} were stored over
(4 Å) MS. TLC was carried out on precoated Macherey–Nagel
plastic sheets Polygram SiO2 N/UV254 (40–80 mm) by using UV
light for visualization. 1H NMR and 13C NMR were recorded with
Bruker spectrometer Avance II (AV 400) [D6]DMSO [δ(1H) =
2.50 ppm], [D6]DMSO [δ(13C) = 39.5 ppm]. IR spectra were mea-
sured with Bruker IFS25 and IFS48 spectrophotometers. HRMS
were recorded with a Sectorfield-MS: Finnigan MAT 95. CHN
analyses were obtained with a Carlo Erba 1106 (balance: Mettler
Toledo UMX-2) analyzer.
better results with alternatively functionalized cata-
lysts.[5a,7b,19] For example, a phase-transfer catalyst bearing
3,4,5-trifluorophenyl substituents leads to higher enantio-
selectivities than a phase-transfer catalyst with pentafluoro-
phenyl substituents[20] possibly due to the lack of polarized
ortho-protons.[21]
Conclusions
As implied in many organocatalytic reactions utilizing 1
and its many derivatives, we find that it readily forms hydro-
gen-bonded complexes with Lewis basic substrates. The
binding interactions do not only arise from interactions of
the highly polar NH protons but also from the ortho-pro-
tons with Lewis bases. This is evident from NMR and IR
spectroscopy, mass spectrometry (ESI), and DFT investi-
gations and bears important implications for catalyst de-
sign.
N,NЈ-Bis[3,5-(trifluoromethyl)phenyl]thiourea (1): To a mixture of
1,1Ј-thiocarbonyldiimidazole[24] (1.50 g, 8.43 mmol) in CH2Cl2
(dried, 8 mL) was added carefully 3,5-bistrifluoromethylaniline
(2.74 mL, 17.70 mmol, 2.1 equiv.) under an argon atmosphere. The
resulting solution was stirred for 24 h at room temperature. The
solvent was evaporated and diethyl ether (70 mL) was added to the
yellowish oil. The organic phase was extracted with HCl (1 m, 3ϫ
20 mL), aqueous NaHCO3 (saturated, 3ϫ 20 mL), and brine (3ϫ
20 mL). The organic phase was dried with Na2SO4. After removing
the drying agent and the solvent, the light yellow solid was recrys-
tallized from CHCl3. The filtrate was concentrated under reduced
pressure, and the residue was recrystallized from CHCl3 again. The
white solid was dried under vacuum in a desiccator over P2O5. A
white solid (2.29 g, 61.3%) was afforded. Physical data were consis-
tent with those reported in the literature.[25]
Experimental Section
General Methods: All chemicals were purchased from Aldrich,
Acros Organics, Alfa Aesar, Merck, and Lancaster in the highest
purity available and were used without further purification unless
otherwise noted. Liquid δ-valerolactone was freshly distilled and
stored in a Schlenk tube under an argon atmosphere in the freezer.
The thiourea and N-crotonyl derivatives were synthesized as noted
below[22] or by literature-known procedures.[13c,23] Thiourea and so-
lid N-crotonyloxazolidinone derivatives were stored under reduced
pressure over P2O5. All solvents used for filtrations were distilled
once. Drying was performed by following established literature pro-
cedures: THF and toluene were freshly distilled from Na/benzo-
phenone ketyl; CH2Cl2 was distilled from CaH2 and stored over
(4 Å) molecular sieves (MS) and under an argon atmosphere. All
N,NЈ-Bis(3,5-dimethylphenyl)thiourea (2): To a mixture of 1,1Ј-thio-
carbonyldiimidazol[24] (1.50 g, 8.43 mmol) in CH2Cl2 (dried, 8 mL)
was added carefully 3,5-dimethylaniline (2.21 mL, 2.14 g,
17.7 mmol, 2.1 equiv.) under an argon atmosphere. The resulting
solution was stirred for 24 h at room temperature. The solvent was
evaporated and ethyl acetate (150 mL) was added to the brown oil;
the solution was poured into a 250-mL separatory funnel. The or-
ganic phase was extracted with HCl (aqueous, 1 m, 3ϫ 40 mL),
aqueous NaHCO3 (saturated, 3ϫ 40 mL), and brine (3ϫ 40 mL).
The organic phase was dried with Na2SO4. After removing the dry-
6
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Hydrogen-Bonding Thiourea Organocatalysts
ing agent and the solvent, the light yellow solid was heated at reflux
in diethyl ether (70 mL in a 250-mL flask) for 0.5 h. The solid was
pumped off and washed with small portions of cooled diethyl ether
–95 °C with liquid nitrogen because at this temperature the solvent
([D8]toluene) froze. Absorbance spectra were recorded at 2 cm–1
resolution (40 scans) with pure solvent at the respective tempera-
to give a white solid (1.38 g, 57.6%). 1H NMR (400 MHz, [D6]- ture as reference.
DMSO): δ = 9.56 (s, 2 H, N-H), 7.04 (s, 4 H, C-Hortho), 6.76 (s, 2
Computational Studies: All computations were performed with the
H, C-Hpara), 2.24 (s, 12 H, CH3) ppm. 13C NMR (100.6 MHz, [D6]-
DMSO): δ = 179.35 (Cq), 139.16 (Cq), 137.39 (Cq), 126.00 (C-H),
Gaussian09 suite of programs.[27] Geometry optimizations and fre-
quency computations were performed using the M06 density func-
tional in conjunction with 6-31+G(d,p) basis set. The M06 func-
tional is recommended for computations of organometallic species
and for studies of noncovalent interactions, thermochemistry, and
kinetics.[11] Additional geometry optimizations and frequency com-
putations for the determination of solvent effects were also per-
formed by using the M06/6-31+G(d,p) method with a self-consis-
tent reaction-field (SCRF) model.[28] SCRF methods treat the sol-
ute at the quantum mechanical level, while the solvent is repre-
sented as a dielectric continuum. Specifically, we chose the polariz-
able continuum model (PCM) developed by Tomasi and co-workers
to describe the bulk solvent.[28,29] PCM computations were modi-
fied by using the UAHF model, a United Atom Topological Model
applied on radii optimized for the HF/6-31G(d) level of theory.[29,30]
We found shifts of the stretching vibrations of the cyclohexyl meth-
ine CH bonds of about ≈100–400 cm–1; at this time the reasons for
these unphysical shifts are unclear, but we note that they only occur
when using the UAHF model in solvent computations. ΔH0 values
are corrected for zero-point vibrational energies (ZPVEs). All com-
puted minima displayed only real vibrational frequencies (no imag-
inary frequencies). The quantum theory of atoms in molecules
(QTAIM)[14] analysis was performed using AIMAll.[15] Computa-
tional results were depicted with CYLview.[31]
121.50 (C-H), 20.93 ppm. IR (KBr disc): ν = 3360.0, 3195.5,
˜
3017.5, 2972.2, 2913.7, 1610.2, 1537.7, 1516.6, 1470.0, 1432.3,
1342.3, 1313.3, 1270.9, 1227.6, 1166.3, 1037.0, 862.2, 847.0, 715.3,
652.3, 482.7 cm–1. HRMS: calcd. for C14H17F3N2S1 [M]+ 284.1347;
found 284.1348.
N-Cyclohexyl-NЈ-[3-(trifluoromethyl)phenyl]thiourea (4): To a 10-
mL flask with a gas inlet charged with dried CH2Cl2 (5 mL) was
added cyclohexylamine (0.3 mL, 0.27 mg, 2.7 mmol) and 3-(tri-
fluoromethyl)phenylisothiocyanate (0.41 mL, 0.55 mg, 2.7 mmol),
and the mixture was stirred at room temperature under an argon
atmosphere for 12 h. Afterwards the solvent was evaporated and
the precipitate was washed with hexane/CH2Cl2 (4:1). The solvent
was then removed. The white solid of 4[26] (0.5 g, 1.64 mmol, 60%)
was dried under vacuum over P2O5. M.p. 140–141 °C. 1H NMR
(400 MHz, [D6]DMSO): δ = 9.59 (s, 1 H, N-H), 8.05 (s, 1 H, C-
Hortho), 7.91 (s, 1 H, N-H), 7.66 (d, J = 7.88 Hz, 1 H, C-Hpara),
7.51 (t, J = 8.9, 8.9 Hz, 1 H, C-Hmeta), 7.39 (d, J = 7.55 Hz, 1 H,
C-Hortho), 4.10 (s, 1 H, C-H), 1.91 (m, 2 H, CH2), 1.69 (m, 2 H,
CH2), 1.51 (m, 1 H, CH2), 1.28 (m, 1 H, CH2) ppm. 13C NMR
(100.6 MHz, [D6]DMSO): δ = 179.18 (Cq), 140.64 (Cq), 129.45 (C-
H), 128.87 (q, J = 30.70 Hz), 125.78 (C-H), 124.01 (q, J =
271.19 Hz), 119.67 (C-H), 118.27 (C-H), 52.07 (C-H), 31.70 (CH2),
25.09 (CH ), 24.42 (CH ) ppm. IR (KBr disc): ν = 3230.8, 3076.2,
˜
MS (ESI) Studies: The formation of thiourea–guest complexes was
also investigated by mass spectrometry using a linear ion trap/
Fourier transform orbital trapping mass spectrometer (LTQ Or-
bitrap Discovery, Thermo Scientific GmbH, Bremen, Germany)
equipped with a nanoelectrospray ion source (Nanospray Ion
Source, Thermo Scientific GmbH, Bremen, Germany).[32] Sample
solutions were prepared by dissolving the host (thiourea derivative
c = 20 mm) and guest (carbonyl derivative c = 20 mm) in toluene
(dried). Analysis was performed in positive ion mode. Complex for-
mation was confirmed by determination of the accurate mass of
the protonated complex and of its constituents (protonated) after
intentional destruction of the complex via collision induced dissoci-
ation (CID).
2
2
2932.7, 2852.9, 1602.4, 1543.3, 1484.8, 1459.3, 1327.4, 1273.3,
1212.0, 1163.8, 1117.3, 1093.0, 1072.8, 984.4, 887.0, 795.5, 715.6,
700.0, 654.8, 588.3 cm–1. HRMS: calcd. for C14H17F3N2S1 [M]+
302.1065; found 302.1088. Elemental analysis: calcd. C 55.61, H
5.67, N 9.26; found C 55.36, H 5.65, N 9.29.
NMR Spectroscopic Data Collection and Processing: The NMR
1
spectra (1H, 13C, H–15N HSQC, NOESY, and ROESY) were re-
corded with a 600 MHz spectrometer equipped with a 5-mm broad-
band z-gradient probe (maximum gradient strength 53.5 Gcm–1).
1
The phase-sensitive H NOESY spectra were recorded by using a
mixing time of 1 s; the ROESY had a spin-lock pulse of 70 ms. The
1H–15N HSQC spectra were acquired with pulsed field gradients.
The delay was adjusted to a coupling constant of 1J(1H,15N) =
60.8 MHz. 1H: 600.13 MHz. 13C: 150.90 MHz; when necessary
using as the internal standard: TMS d(1H) = 0, d(13C) = 0, [D8]-
toluene [δ(1H) = 2.09, 6.98, 7.00, 7.09 ppm], [D8]toluene [δ(13C) =
18.3, 25.2, 78.7 ppm], [D8]THF [δ(1H) = 1.73, 3.58 ppm], [D8]THF
[δ(13C) = 25.37, 67.57 ppm]. 19F–1H HOESY measurements were
X-ray Crystallographic Analysis: CCDC-868394 (for 2), -868395
(for 4), and -206506 (for 1) contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif. The crystal structure of 1
was previously published by Kotke and Schreiner.[25]
performed with
a 400 MHz Bruker Avance II spectrometer
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details, remarks on NMR spectroscopic data
collection and processing, matrix isolation studies, computational
studies, as well as all NMR, IR, matrix-isolation IR, and mass
spectra.
equipped with a 5-mm BBFO probe with z-gradient. For the 19F–
1H HOESY experiments the hoesyph pulse sequence was used and
1 K data points were acquired in the directly detected dimension.
All experiments were run under fluorine detection. A mixing time
of 800 ms was used for the non-degassed samples and 64 scans were
taken for each of the 256 T1 increments. The delay between in-
crements was set to 3 s. The 19F signals are recorded relative to the
resonance of a sample of CFCl3.
Acknowledgments
This work was supported by the Deutsche Forschungsgemein-
schaft. We thank Robert E. Rosenberg (Transylvania University,
Kentucky, USA), Jörg Glatthaar, and Hans Peter Reisenauer (JLU)
for their help and stimulating discussions. We thank Jens Breden-
beck and Andreas T. Messmer (Johann Wolfgang von Goethe Uni-
versity, Frankfurt) for discussions.
IR Spectroscopic Studies: We used a Bruker IFS 25 IR or a Bruker
IFS 55 FTIR spectrometer and a low-temperature cell with CaF2
windows. Solutions of the various pure compounds and compound
mixtures in [D8]toluene were loaded into a low-temperature CaF2
cell (d = 0.1 mm). The cell was cooled from room temperature to
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P. R. Schreiner et al.
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Hydrogen-Bonding Thiourea Organocatalysts
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Received: June 1, 2012
Published Online: ᭿
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Job/Unit: O20739
/KAP1
Date: 10-09-12 16:13:18
Pages: 10
P. R. Schreiner et al.
FULL PAPER
Organocatalysis
The present work reveals that thiourea de-
rivatives bearing a 3,5-bis(trifluoromethyl)-
phenyl group interact with Lewis basic sites
of carbonyl derivatives through NH and
highly polarized ortho-CH interactions in
hydrogen-bonded complexes. Evidence is
provided through a combination of DFT,
variable-temperature IR and NMR spec-
troscopy, as well as MS (ESI) studies.
K. M. Lippert, K. Hof, D. Gerbig, D. Ley,
H. Hausmann, S. Guenther,
P. R. Schreiner* .............................. 1–10
Hydrogen-Bonding Thiourea Organocata-
lysts: The Privileged 3,5-Bis(trifluoro-
methyl)phenyl Group
Keywords: Density functional theory com-
putations / IR spectroscopy / NMR spec-
troscopy / Organocatalysis / Thiourea de-
rivatives
10
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