Understanding reactivity and stereoselectivity in palladium-catalyzed diastereoselective sp3 C-H Bond activation: Intermediate characterization and computational studies

Article abstract of DOI:10.1021/ja304643e

The origin of the high levels of reactivity and diastereoselectivity (>99:1 dr) observed in the oxazoline-directed, Pd(II)-catalyzed sp ³ C-H bond iodination and acetoxylation reactions as reported in previous publications has been studied and explained on the basis of experimental and computational investigations. The characterization of a trinuclear chiral C-H insertion intermediate by X-ray paved the way for further investigations into C-H insertion step through the lens of stereochemistry. Computational investigations on reactivities and diastereoselectivities of C-H activation of t-Bu- and i-Pr-substituted oxazolines provided good agreement with the experimental results. Theoretical predictions with DFT calculations revealed that C-H activation occurs at the monomeric Pd center and that the most preferred transition state for C-H activation contains two sterically bulky t-Bu substituents in anti-positions due to steric repulsion and that this transition state leads to the major diastereomer, which is consistent with the structure of the newly characterized C-H insertion intermediate. The structural information about the transition state also suggests that a minimum dihedral angle between C-H bonds and Pd-OAc bonds is crucial for C-H bond cleavage. We have also utilized density functional theory (DFT) to calculate the energies of various potential intermediates and transition states with t-Bu- and i-Pr-substituted oxazolines and suggested a possible explanation for the substantial difference in reactivity between the t-Bu- and i-Pr-substituted oxazolines.

Full text of DOI:10.1021/ja304643e

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Article
Understanding Reactivity and Stereoselectivity in Palladium-
Catalyzed Diastereoselective sp3 C–H Bond Activation:
Intermediate Characterization and Computational Studies
Ramesh Giri, Peng Liu, Yu Lan, K. N. Houk, and Jin-Quan Yu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja304643e • Publication Date (Web): 25 Jul 2012
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Understanding Reactivity and Stereoselectivity in
Palladium-Catalyzed Diastereoselective sp3 C–H Bond
Activation: Intermediate Characterization and
Computational Studies
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Ramesh Giri, † Yu Lan, ‡ Peng Liu, ‡ K. N. Houk*‡ and Jin-Quan Yu*†
†Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla,
California 92037 ‡Department of Chemistry and Biochemistry, University of California, Los Angeles,
California 90095.
yu200@scripps.edu; houk@chem.ucla.edu
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
†The Scripps Research Institute
‡University of California
Abstract. The origin of the high levels of reactivity and diastereoselectivity (>99:1 dr) observed in the
oxazoline-directed, Pd(II)-catalyzed sp3 C–H bond iodination and acetoxylation reactions as reported in
previous publications has been studied and explained based on experimental and computational
investigations. The characterization of a trinuclear chiral C–H insertion intermediate by X-ray paved the
way for further investigations into C–H insertion step through the lens of stereochemistry.
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Computational investigations on reactivities and diastereoselectivities of C–H activation of t-Bu- and i-
Pr-substituted oxazolines provided good agreement with the experimental results. Theoretical
predictions with DFT calculations revealed that the most preferred transition state for C–H activation
contains these two sterically bulky t-Bu substituents in anti-positions due to steric repulsion, and that
this transition state leads to the major diastereomer which is consistent with the structure of the newly
characterized C–H insertion intermediate. The structural information about the transition state also
suggests that a minimum dihedral angle between C–H bonds and Pd–OAc bonds is crucial for C–H
bond cleavages. We have also utilized density functional theory (DFT) to calculate the energies of
various potential intermediates and transition states with t-Bu and i-Pr substituted oxazolines, and
suggested a possible explanation for the substantial difference in reactivity between the t-Bu and i-Pr
substituted oxazolines. 
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1. Introduction
Transition metal-catalyzed activation/functionalization of unactivated C–H bonds has been the subject
of great research interest in recent years.1, 2 Among the plethora of transition metal-catalyzed processes,
palladium-catalyzed reactions, in particular, have enjoyed a prominent standing in the C–H activation
field.3 In addition to innovation of diverse reactions, detailed mechanistic pathways, particularly
concerning the discrete steps involved in the catalytic processes, are being meticulously investigated
from both theoretical standpoints4, 5, 6, 7 and experimental studies.8, 9 Despite remarkable progress in
these two frontiers with palladium catalysts, stereoselective cleavage of unactivated prochiral C–H
bonds and its mechanistic aspects have been little explored.10 The diastereotopic CH bonds at the
carbon atom are selectively cleaved on a metal center under the influence of a proximal chiral center
tethered to it via a removable linkage.11 Tolman and coworkers observed a moderate level of
diastereoselectivity in the intramolecular activation of sp3 CH bonds in a rhodium dicarbonyl complex
of C3-symmetric TpMenth ligand.12 Although these metal-mediated reactions show stereoselectivity
during the CH activation step, subsequent functionalization of the metallacycles has been realized only
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in limited cases. Sames and coworkers have described the total synthesis of (–)-rhazinilam based on the
diastereoselective dehydrogenation of an ethyl group via CH activation by attaching a synthetic
intermediate to a stoichiometric dialkyl Pt-chiral oxazoline complex through an imine linkage.13
Tremendous efforts have also been devoted to develop transition metal-catalyzed asymmetric CH
functionalization in the areas of allylic acetoxylation,14 biomimetic oxidation,15 addition of arene to
alkene16 and carbenoid/nitrenoid insertion.2, 17 In this regard, we reported a rare example of auxiliary-
controlled asymmetric Pd insertion into both sp2 and sp3 CH bonds. Selection of an appropriate
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auxiliary or directing group that would effect CH bond cleavage with palladium catalysts under mild
conditions is crucial for high stereoselectivity. While asymmetric induction through installation of chiral
auxiliary is a well-established procedure in organic synthesis,18 extension of this approach to the
catalytic, stereoselective activation of CH bonds is largely unexplored. We were encouraged by
Meyer’s -lithiation/alkylation chemistry, where chiral oxazolines provide high levels of asymmetric
induction,19 and the success of using chiral oxazolines as ligands in asymmetric catalysis.20
Furthermore, previously observed oxazoline-directed cyclopalladation reactions of both sp2 and sp3
CH bonds21 also provided the foundation for our exploratory studies.
We began our investigation by proposing a working steric model for diastereoselective cleavage of
CH bonds on organic molecules pre-coordinated to a transition metal through a removable, non-
racemic, chiral linkage (Scheme 1). Since -chelation-assisted CH activation takes place through a
cyclic transition state,5 we envisioned that the selection of oxazoline as a cyclic chiral auxiliary would
provide an efficient stereocontrol by forming a conformationally rigid bicyclic transition state 1 during
CH bond cleavage. As a consequence, the chiral auxiliary could induce high levels of stereoselectivity
during CH activation in conjunction with a bicyclic conformation via a steric repulsion model outlined
in Scheme 1. Transition state 1a, in which the sterically bulky R1 and R2 groups are in anti-position, is
favored over 1b due to reduced steric repulsion between Me and R2 when R1 is larger than the Me
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group. Predominant C–H activation pathway through transition state 1a will give the major
stereoisomer.
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Scheme 1. Working model for diastereoselective C–H cleavage
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Our early investigations were long baffled by the lack of reactivity and stereoselectivity of oxazolines
bearing 4-i-Pr group such as 2c (R1 = Et, R2 = i-Pr; 15% yield, 0% de) for the iodination of -CH
bonds (Scheme 2). Strikingly, reactions proceeded with high yields and moderate diastereoselectivity
when the 4-i-Pr group was replaced by a 4-t-Bu group (2b, R1 = Et, R2 = t-Bu; 91% yield, 25% de).
Moreover, substitution of Et group at the -position of the parent carboxylic acid with sterically
demanding t-Bu group, such as in oxazoline 2a, afforded mono-iodinated product 3a in 83% yield with
a high level of diastereoselectivity (82% de) (Scheme 2).
Intrigued by the dramatic change in reactivity and stereoselectivity with subtle alterations in the steric
environment on the oxazoline ring, we have sought, in the present study, to elucidate the mechanism
and origin of reactivity and diastereoselectivity through the preparation and characterization of a
reactive intermediate formed after diastereoselective CH activation, and computational studies on the
energies of possible intermediates and transition states leading to the isolated intermediate using density
functional theory (DFT).22 Our computational investigation has revealed that the reactions with i-Pr and
t-Bu-substituted oxazolines involve different catalyst resting states before C–H activation, and that the
lower reactivity of an i-Pr-substituted oxazoline results from greater stability of its catalyst resting state,
which accounts for higher overall activation barrier for C–H cleavage. We have also characterized by a
single crystal X-ray crystallography the major isomer of a chiral trinuclear palladacycle formed after
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diastereoselective cleavage of a -C–H bond of a chiral oxazoline bearing two diastereotopic methyl
groups. In excellent agreement with the solid state structure, theoretical predictions with density
functional theory (DFT) calculations also revealed that the most preferred transition state for C–H
activation in oxazoline substrates contains sterically bulky substituents at the -position of parent
carboxylic acid and the oxazoline ring in anti-positions due to steric repulsion, and that this transition
state leads to the major diastereomer.
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Scheme 2. Diastereoselective CH iodination with i-Pr and t-Bu substituted oxazoline auxiliaries
2. Results and Discussion
We previously prepared the cyclopalladated trinuclear complexes 5, 6 and 8 of achiral and chiral
oxazolines 4 and 7 (Scheme 3).9, 23 These palladacycles are potential intermediates in the Pd(II)-
catalyzed iodination and acetoxylation of unactivated CH bonds.9 First, these palladacycles maintain
trinuclear integrity in the reaction solvent (CH2Cl2). The trinuclear complexes distinguish themselves
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from dimer and monomer by the ratio of acetate groups to oxazoline units as indicated by H NMR.
Second, they react with iodine and peroxide/acetic anhydride at room temperature to afford the
iodinated and acetoxylated products in high yields. Examination of the X-ray crystal structures of these
highly reactive trinuclear Pd(II)-complexes 5 and 8 led us to propose a stereomodel to account for
diastereoselectivity.24 In sharp contrast to the 3:2 mixture of anti- and syn-complexes 5 and 6 formed
from achiral oxazoline 4, only the anti-isomer 8 was obtained from the chiral oxazoline 7. However, we
had not characterized intermediates that contain chiral centers on both auxiliary and substrate, which are
crucial for elucidating the stereomodel and transition state.
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Scheme 3. Trinuclear Pd(II)-complexes with achiral and chiral oxazolines
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To gain insights into the absolute stereochemistry of the observed CH activation, we prepared the
cyclometallated intermediate 9a from the reaction of Pd(OAc)2 with the chiral oxazoline 2a containing
diastereotopic methyl groups on the parent carboxylic acid moiety (Scheme 4). The complex 9a
contains a mixture of isomers in a 91:9 ratio, which approximately corresponds to the observed
diastereoselectivity. The complex 9a is highly soluble in n-pentane even at 18 ºC, and its purification
and crystallization proved extremely difficult. However, we discovered that the bridging -acetato
groups could be easily exchanged with -trifluoroacetato groups without losing the stereoisomeric ratio
(91:9) by simply stirring the complex 9a in trifluoroacetic anhydride for 24 h at room temperature. We
were then able to isolate palladacycle 10a with bridging -trifluoroacetato groups and grow a single
crystal at 18 °C, which was characterized to be the major isomer syn-(S,S)-10a by X-ray
crystallography. As predicted, the t-Bu groups on the carboxylic acid and oxazoline moieties were
oriented in anti-positions at both termini of the trinuclear palladacycle syn-(S,S)-10a. As a result, the
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newly generated chiral center assumed (S)-configuration.25 Moreover, the reaction of -acetato
palladacycle 9a with iodine affords the iodinated product in the same diastereoisomeric ratio (91:9).
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Scheme 4. Determination of absolute stereochemistry of CH activation
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Figure 1. ORTEP diagram of palladacycle syn-(S,S)-10a. Selected bond lengths (Å) and angles (deg):
C1–Pd1, 1.991(8); C23–Pd3, 1.994(8); N1–Pd1, 2.001(6); N2–Pd3, 2.023(6); Pd1–Pd2, 2.9458(8);
Pd2–Pd3, 2.9539(8); C1–Pd1–N1, 81.0(3); C23–Pd3–N2, 83.1(3).
To further investigate the effects of substituents on reactivity and the origin of the high level of
diastereoselectivity during the C–H bond cleavage, we performed density functional theory (DFT)
studies to calculate the energies of different intermediates and transition states leading to the formation
of trinuclear intermediate 9. Despite extensive computational studies on C–H cleavage involving
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ArPdX(PPh3) species by Maseras and Echavarren,4 and Fagnou,6 understanding of cyclopalladation
reactions with Pd(II) catalysts remains less developed. In an early mechanistic study of aryl C–H
cyclopalladation, Martinez proposed a proton abstraction pathway involving a four-membered transition
state.26 Subsequent computational work by Davies and Macgregor in 2005 supported a similar
mechanism, but involving a six-membered transition state.5 These computational studies indicated that a
vacant coordination site on palladium is necessary for insertion into the C–H bond. Based on these
previous mechanistic studies, a proposed mechanism of the formation of trinuclear palladacycle 9 is
outlined in Scheme 5. The Pd3(OAc)6 trimer27 reacts with two molecules of oxazoline 2 to generate
intermediate 11, which dissociates upon further coordination with 2 to form monomeric intermediates
12 or 13 with either one or two oxazolines bound to Pd. The Pd in 12 and 13 adopts a square planar
geometry. In intermediate 13, one of the acetato groups is -2 coordinated to palladium while the other
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acetato is -1 coordinated. The -2 acetato isomerizes to be -1 coordinated and releases a vacant
coordination site on Pd for subsequent C–H activation. In the C–H activation transition state 14-ts, the
cleavage of C–H bond and formations of the Pd–C and AcO–H bonds are concerted. The structure of
14-ts suggests that maintaining a minimum dihedral angle between C–H bonds and Pd–OAc bonds are
essential for high reactivity. The C–H activation leads to a monomeric palladacycle intermediate 15.
After the release of acetic acid, the trimeric palladacycle complex 9 is generated. Alternatively, the C–H
activation may occur with the Pd trimer 11 via transition state 17-ts instead of its dissociation to
monomeric Pd species before C–H activation. This requires breaking one of bridged acetato groups to
generate a free coordination site on Pd for C–H activation. Both pathways were considered in the
computational investigations.
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Scheme 5. The proposed mechanism of the Pd(OAc)2 catalyzed C–H activation of oxazoline 2.
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The free energy profiles of C–H activation of oxazolines 2a (R1 = t-Bu, R2 = t-Bu) and 2c (R1 =
Et, R2 = i-Pr) are shown in Figure 2. Coordination of two molecules of oxazoline 2c to the Pd3(OAc)6
trimer to form complex 11c is exergonic by 6.8 kcal/mol. The same process with bulkier oxazoline 2a to
form 11a is endergonic by 9.3 kcal/mol. Further coordination of oxazoline 2c leads to decomposition of
complex 11c to form monomeric [bis(oxazoline)]Pd(OAc)2 complex 12c, which is 10.4 kcal/mol more
stable than Pd3(OAc)6. In the reaction with oxazoline 2a, the Pd monomer complex 12a is 2.5 kcal/mol
less stable than Pd3(OAc)6. Dissociation of one molecular oxazoline from 12a and 12c to form 13a and
13c are endergonic by 6.9 and 17.1 kcal/mol, respectively. Thus, in the reaction with the bulkier
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oxazoline 2a, the catalyst resting state before C–H activation is Pd3(OAc)6, while in the reaction with
2c, the resting state is the monomeric [bis(oxazoline)]Pd(OAc)2 complex 12c. The stability of the
resting state 12c leads to significantly higher overall activation energies for C–H activation of oxazoline
2c. Although the C–H activation transition state 14c-ts is only 1.8 kcal/mol less stable than the 14a-ts,
the overall activation barrier for reaction with 2c is 38.4 kcal/mol (12c  14c-ts), much higher than that
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for the reaction with 2a in which the overall barrier is 26.2 kcal/mol (Pd3(OAc)6  14a-ts). The C–H
activation leads to the five-membered metallacycle intermediate, 15a, and 15c, respectively. Subsequent
elimination of acetic acid from 15a and 15c leads to 16a and 16c, both are a few kcal/mol less stable
than 15a/c in terms of Gibbs free energies. Association of two molecules of 16a/c and Pd(OAc)2 forms
stable trinuclear Pd metallacycles 9a and 9c. Both 9a and 9c are ~11 kcal/mol more stable than the
monomeric metallacycle 15a and 15c. We have also computed single point solvation energy corrections
using the SMD model and the results are summarized in the supporting information. In the solvation-
corrected free energy diagram, the maximum deviations from the gas-phase results are within a few
kcal/mol. The relative activation free energies in gas-phase and in solution only differ by a few tenth of
a kcal/mol. These solvation effects do not change any conclusions of the gas phase results.
The alternative pathway which involves C–H activation directly from the trinuclear complexes
11a and 11c is less favorable than the mononuclear pathway described above. Trinuclear C–H activation
transition states 17a-ts and 17c-ts are 7.2 and 3.1 kcal/mol less favorable than the corresponding
mononuclear C–H activation transition states (14a-ts and 14c-ts, respectively). The C–H activation from
the trinuclear complex requires breaking one of the bridged acetato groups to generate a free
coordination site on Pd. This leads to the higher activation energies of the trinuclear pathway.
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Figure 2. The M06 free energy profile of C–H activation of oxazolines 2a (blue) and 2c (red).
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Enthalpies are given in parentheses.
12a (∆G = 2.5 kcal/mol)
12c (∆G = –10.4 kcal/mol)
Figure 3. Optimized geometries of [bis(oxazoline)]Pd(OAc)2 complexes 12a and 12c. Energies are with
respect to Pd3(OAc)6.
The optimized geometries of the bis(oxazoline) Pd-complexes 12a and 12c are shown in Figure
3. Complex 12a is destabilized due to steric repulsions of the t-Bu (R2) groups with the acetate. In 12a,
the shortest O–H distances between the t-Bu hydrogen and acetate oxygen atoms are 2.21 and 2.43 Ǻ.
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Replacing the t-Bu group with an i-Pr group, the complex 12c is much less crowded, and thus more
stable than 12a.
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We then investigated the origin of stereoselectivity in C–H activations of oxazolines 2a-c. For
each oxazoline, the C–H activation may occur via four possible transition states (14-ts1 – 14-ts4,
Scheme 6). The optimized geometries of the C–H activation transition states with oxazoline 2a are
shown in Figure 4. All four transition states involve simultaneous cleavage of the C–H bond and
formation of the AcO–H and Pd–C bonds as well as strong Pd–H interaction, which indicate a concerted
metalation-deprotonation mechanism and a rigid cyclic transition state structure. The six-membered
cycle that involves Pd, two atoms in the oxazoline ring, the prochiral -carbon, and the C–H bond being
cleaved, adopts a half-chair conformation. In 14-ts1 and 14-ts3, the proton being transferred is above
the Pd-oxazoline plane, and the -substituent that is syn to R2 (Me and R1 in 14-ts1 and 14-ts3,
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respectively) is at the axial position. In 14-ts2 and 14-ts4, the syn -substituent is equatorial (Me and R1
in 14-ts2 and 14-ts4, respectively). The R1 and R2 groups are anti to each other in 14-ts1 and 14-ts2,
which lead to the major diastereomeric (S,S)-product. R1 and R2 are syn in 14-ts3 and 14-ts4, leading to
the minor (S,R)-diastereomer. The computed relative activation energies are summarized in Table 1. In
the reactions with 2a and 2b, 14-ts1 and 14-ts3 are more than 2 kcal/mol less stable than 14-ts2 and 14-
ts4. Transition states 14-ts1 and 14-ts3 are destabilized by steric repulsions between the axial
substituents on the -carbon and the t-Bu (R2) on the oxazoline. When a smaller R2 group (i-Pr) is
employed, 14c-ts1 and 14c-ts3 are only a few tenths kcal/mol less stable than 14c-ts2 and 14c-ts4. In
the reactions with all three oxazolines, the diastereoselectivity of the C–H activation product is
determined by the energy difference between 14-ts2 and 14-ts4. In the reaction with 2a, 14a-ts2 is 2.3
kcal/mol more stable than 14a-ts4. This suggests the syn product (S,S)-15a is favored with 96% de. In
the reactions with 2b and 2c, the energy difference between 14-ts2 and 14-ts4 is diminished, in
agreement with the low de observed in experiment.
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Scheme 6. Possible transition states of the C–H activation.
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14a-ts1
14a-ts2
∆∆G‡ = 5.0 kcal/mol
∆∆G‡ = 0.0 kcal/mol
14a-ts3
14a-ts4
∆∆G‡ = 3.8 kcal/mol
∆∆G‡ = 2.3 kcal/mol
Figure 4. Optimized geometries of transition states 14a-ts1, 14a-ts2, 14a-ts3, and 14a-ts4 and the
Newman projections about the C–C bond highlighted in green.
Table 1. Relative activation free energies and enthalpies (in parentheses) for the C–H activation
transition states. All energies are with respect to 14-ts2 in kcal/mol.
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oxazoline R1
R2
de (calc.)
2.3 (2.2) 96% (96%)
0.1 (0.2) 8% (17%)
de (exp.)
14-ts1
14-ts2
14-ts3
3.8 (3.4)
3.6 (3.0)
14-ts4
1
2
3
4
t-Bu t-Bu 5.0 (4.7)
0.0 (0.0)
0.0 (0.0)
0.0 (0.0)
82%
25%
0 %
2a
2b
2c
Et
Et
t-Bu 2.8 (3.0)
i-Pr 0.3 (0.6)
0.8 (0.5) -0.2 (-0.1) 17% (8%)
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9
The energy difference between 14a-ts2 and 14a-ts4 is attributed to the gauche-t-Bu/H repulsions
around the prochiral carbon–methyl bond (highlighted in green in Figure 4). The cleaving C–H bond is
gauche to the adjacent t-Bu group in 14a-ts2 and anti to the t-Bu in 14a-ts4 (see the Newman
projections in Figure 4). Because the C–H distances in the cleaving C–H bond (~1.4 Å) is significantly
longer than a regular C–H bond (~1.1 Å), the gauche t-Bu/H repulsion with the cleaving C–H bond is
smaller. In 14a-ts2, there is one regular gauche t-Bu/H interaction with an H–H distance of 2.27 Å
between t-Bu and He. The gauche repulsion with the cleaving C–H' bond is much weaker, with a
significantly longer H–H distance of 2.38 Å between t-Bu and H'. In contrast, there are two hydrogens
gauche to the t-Bu in 14a-ts4, with H–H distances being 2.14 and 2.22 Å, respectively. Thus, 14a-ts4 is
less stable than 14a-ts2 due to unfavorable gauche t-Bu/H repulsions. Replacing the t-Bu (R1) group
with smaller Et, the energy differences between transition states 14b-ts2 and 14b-ts4 and between 14c-
ts2 and 14c-ts4 reduced to essentially zero, in agreement with experiment. The gauche repulsions
between Et and H are much smaller than the t-Bu/H repulsions. The Et substitution on R1 is not
sufficient to differentiate the activation of anti and gauche C–H bonds as illustrated in the Newman
projections in Figure 4.
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3. Conclusions
We have prepared and characterized the major diastereomer of a chiral trinuclear palladacycle that
exists as a potential intermediate in the oxazoline-directed, Pd(II)-catalyzed iodination and acetoxylation
of sp3 C–H bonds. Reaction of the chiral trinuclear palladacycle with I2 provided the iodinated product
in the same diastereomeric ratio as that of the catalytic reaction (dr, 91:9). The solid state structure of
the major diastereomer syn-(S,S)-10a revealed that the two bulky t-butyl groups on the oxazoline and
carboxylic moieties of the substrate remain in anti-positions to each other, and that the new chiral center
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generated after the C–H cleavage assumed (S) stereochemistry. Computational investigations on
reactivities and diastereoselectivities of C–H activation of oxazolines 2a-c provided good agreement
with the experimental results. In the most preferred transition state, in which the bulky t-Bu substituents
on the prochiral carbon (R1) and on the oxazoline (R2) prefer to be anti to each other, leads to the major
diastereomer product syn-(S,S)-10a. t-Bu substitution at the R2 position is essential to achieve high
reactivity. Replacing the R2 group with the smaller Et group leads to formation of a stable resting
[bis(oxazoline)]Pd(OAc)2 complex before the C–H activation and increases the overall activation
barrier. In the reaction with t-Bu substituted oxazoline 2a, such [bis(oxazoline)]Pd(OAc)2 complex is
destabilized to form the reactive monomeric intermediate (oxazoline)Pd(OAc)2 due to steric repulsions
with the t-Bu groups.
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4. Experimental
4.1. Preparation of Trinuclear Bis-μ-acetato and Bis-μ-trifluoroacetato Pd(II) Complexes 9a
and 10a. Oxazoline 2a (113 mg, 0.5 mmol) was stirred with palladium acetate (168 mg, 0.75 mmol) in
CH2Cl2 (5 ml) at 24 °C for 48 h. The solvent was removed in a rotary evaporator to give a pale green
complex 9a. This complex is highly soluble in n-pentane even at 18 ºC. The crude complex 9a was
stirred in trifluoroacetic anhydride (1 mL) for 24 h at room temperature. The excess of anhydride was
removed in a rotary evaporator and the residue was washed with cold n-pentane (0.2 mL × 2) and dried
under high vacuum to afford a green complex 10a as a mixture of two isomers in a 91:9 ratio (225 mg,
84% yield). The complex was characterized by NMR spectroscopy. 1H NMR (400 MHz, CD2Cl2)  0.92
(s, 9H × 0.91), 1.02 (s, 9H), 1.05 (s, 9H × 0.09), 1.32 (s, 3H × 0.09), 1.46 (s, 3H × 0.91), 2.34 (d, J = 8.0
Hz, 1H × 0.91), 2.52 (d, J = 8.0 Hz, 1H × 0.09), 3.00 (d, J = 8.0 Hz, 1H × 0.09), 3.37 (d, J = 8.0 Hz, 1H
× 0.91), 3.46 (d, J = 8.0 Hz, 1H), 4.21 (t, J = 8.0 Hz, 1H × 0.91), 4.27 (t, J = 8.0 Hz, 1H × 0.09), 4.56 (d,
13
J = 8.0 Hz, 1H); C NMR (100 MHz, CD2Cl2)  14.0, 21.5, 22.5, 23.8, 24.9, 25.6, 25.8, 25.9, 26.0,
26.1, 34.4, 34.5, 34.7, 35.3, 50.4, 51.1, 70.3, 70.8, 71.2, 71.3, 184.9, 185.5.
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4.2. Crystallization of syn-(S,S)-10a. The complex 10a was dissolved in n-pentane at room
temperature and filtered through a Cameo 3N syringe filter (0.45 µ, 3 mm) (Osmonics Inc.) in a glass
sample vial. The complex was crystallized as green prisms in 24 hours at 18 °C. The green prismatic
crystals were characterized by X-ray crystallography.
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4.3. Computational Methodology. Geometries were optimized with B3LYP and the SDD basis set
for Pd and the 6-31G(d) basis set for other atoms. Single point energies were calculated at the
M06/SDD–6-311++G(d,p) level. The reported free energies and enthalpies include zero-point energies
and thermal corrections calculated at 298K with B3LYP/SDD–6-31G(d). All calculations were
performed with Gaussian 09.28
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Acknowledgement. We gratefully acknowledge TSRI and NSF Center for Stereoselective C–H
Functionalization (CHE-0943980) and the National Science Foundation (CHE-1059084, KNH) for
financial support of this research. Calculations were performed on the Hoffman2 cluster at UCLA and
the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by the
NSF.
Supporting Information Available. Experimental procedures, characterization of the complex syn-
(S,S)-10a, complete ref. 28 and computational details. This material is available free of charge via the
internet at http://pubs.acs.org.
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diastereomers.
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(R = CF3, X-ray)
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