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sxzzg

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[求助] 各位大侠翻译一篇英文

翻译776-777页
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1楼 2014-01-21 08:32:53
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feixiaolin

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建议你把关键片段复制成word 文本挂上来。
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2楼2014-01-21 09:16:13
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dailun20

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这里不接受全文翻译哦，谢谢！如果需要帮忙的话，可以想2楼斑竹说的那样，给出重点需要翻译的就行了~
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3楼2014-01-21 15:11:56
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sxzzg

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During the development of the oral anticoagulant Apixaban4
(6, Scheme 1), we were compelled to gain further insights into
the  key  amidation  step  in  order  to  optimize  the  reaction
outcome  and  build a  predictive  kinetic  model.5 Of  central
interest to the process team was the evaluation of critical kinetic and thermodynamic parameters to enable optimal control of reaction rates and yields. Herein we report mechanistic studies that shed light on the underlying complexities of the ester amidation promoted by sodium formamide.
We began investigating the MeONa-mediated deprotonation of formamide in DMF (eq 1).6  The use of a ReactIR system allowed us to monitor the disappearance of formamide (1710 cm−1) and concomitant formation of its sodium salt  (1580 cm−1).7 The  deprotonation  occurred  instantaneously  upon
addition of MeONa at 0 °C8 to afford Keq  = 25 ± 5, indicating
that under the reaction conditions  (24  equiv of formamide
relative to MeONa) sodium formamide is the major sodium-
bearing species in solution (>99.8 mol %).9  Next, we explored
the equilibria generally represented in eq 2 by completing a
sequence of control experiments. Reaction of carboxamide 6 in
the absence of formamide with excess sodium diformylamide10
in DMF/MeOH afforded mixtures of carboxamide 6 and ester
4 with [6]/[4] ratios that decreased at higher concentrations of added sodium diformylamide (Figure 1a). Submission of the protonated  form  of  N-acylformamide 5 to  the  reaction
conditions  resulted  in  instantaneous  conversion  to  give
mixtures of carboxamide 6 and ester 4 with increasing [6]/
[4] ratios at higher formamide/MeOH proportions  (Figure
1b). These observations support a reversible amidation that requires  excess  formamide  to  promote  the  formation  of carboxamide 6.
Kinetic studies on the amidation of ester 4 were performed
using the method of initial rates11  in the presence of excess
sodium  formamide  and  formamide  relative  to  MeOH  to
effectively  trap  N-acylformamide 5.  HPLC  analyses  of  the
reaction  mixtures  revealed  a  clean  decay  of  ester 4        and
simultaneous  formation  of  carboxamide 6  along  with  trace
amounts  of  the  steady-state  intermediate 5        in  isolated
experiments.12 A  kinetic  isotope  effect  kH/kD =  1.4  ±  0.1
determined by comparing amidations in formamide/MeOH
and formamide-d3/MeOD mixtures is consistent with solvent
participation in the reaction coordinate. Monitoring the decay
of 4 over a range of substrate, sodium formamide, formamide,
and MeOH concentrations using DMF as the cosolvent affords
first-order dependencies in substrate and sodium formamide
along with saturation kinetics in formamide and MeOH
2). Within the saturation regime in solvent, the reaction orders
are consistent with the rate law in eq 3 and the general rate-
determining step in eq 4, where m denotes the aggregation state
of sodium formamide, S represents the coordinating solvents,
and n defines the solvation number.13 The rate dependencies at
low MeOH and formamide concentrations will be discussed in
the context of computational studies below.
rate =k ′[4]1[HCONHNa]1[MeOH]0[HCONH2]0        (3)
[(HCONHNa)m Sn]        +        4
→        [(HCONHNa)m Sn(4)]        ≠        (4)
A Hammett plot for the analogous amidation of p-substituted
methyl benzoates gives ρ = 2.2 ± 0.3, indicating the transfer of
negative charge from sodium formamide to ester 4 in the rate-

Figure 1. (a) Plot of [6]/[4] molar ratios versus [(CHO)2NNa] for
the conversion of carboxamide 6 (0.011 M) to ester 4 in 6.5 M DMF/ MeOH  after  24  h  at  20  °C.  (b)  Plot  of  [6]/[4]  ratios  versus formamide mole fraction (χ) for the reaction of N-acylformamide 5 (0.010  M) with MeONa  (0.67  M) in formamide/MeOH mixtures after 24 h at 20 °C.
experiments.12 A  kinetic  isotope  effect  kH/kD =  1.4  ±  0.1
determined by comparing amidations in formamide/MeOH
and formamide-d3/MeOD mixtures is consistent with solvent
participation in the reaction coordinate. Monitoring the decay
of 4 over a range of substrate, sodium formamide, formamide,
and MeOH concentrations using DMF as the cosolvent affords
first-order dependencies in substrate and sodium formamide
along with saturation kinetics in formamide and MeOH (Figure

























Figure 2.  Plots  of  initial  rates  for  the  amidation  of  ester 4  by
HCONHNa at 0 °C versus (a) [4], (b) [HCONHNa], (c) [MeOH],
(d) [HCONH2]. Rate dependencies on [4] and [HCONHNa] were
measured in  [MeOH]  =  0.46  M and  [HCONH2]  =  4.8  M. Rate
dependencies on [MeOH] and [HCONH2] were measured using [4]
= 0.004 M and [HCONHNa] = 0.027 M in [HCONH2] = 4.8 M and
[MeOH]  =  0.11  M, respectively. Additional data are included in
Supporting Information.
2). Within the saturation regime in solvent, the reaction orders
are consistent with the rate law in eq 3 and the general rate-
determining step in eq 4, where m denotes the aggregation state
of sodium formamide, S represents the coordinating solvents,
and n defines the solvation number.13 The rate dependencies at

determining transition state.14
We investigated the amidation of model substrate 7 using
DFT calculations at the B3LYP/6-31+G(d) level of theory. A
series of geometries were tested for reactants, intermediates,
and transition structures, and the optimized structures were
submitted to single-point MP2/6-31+G(d) calculations incor-
porating thermal corrections to Gibbs free energy as obtained
from the frequency analysis at the B3LYP/6-31+G(d) level and PCM corrections for formamide as the solvent (ΔG, 298.15 K, 1.0  atm).15 Admittedly, the choice of implicit solvation and
monomeric  sodium  formamide  to  simplify the  unattainable
combination of aggregates and solvates provides results that
must be interpreted with caution. The discussion will focus on
three aspects: (i) the deprotonation of formamide,  (ii) the
nature of the rate-determining transition structure, and (iii) the evaluation of the kinetically obscure formyl transfer.
The computational study of the reaction between MeONa and formamide reveals a barrierless and exothermic deproto-
nation (ΔG = −5.5 kcal•mol−1),  in  agreement  with
experimental  results (Scheme  2).  Transition  structure  TS1
displays an optimal geometry for the proton transfer with a
planar  six-membered  ring  and  a  virtually  linear  N−H−O
angle.16
The  lowest  energy  pathway  calculated  for  the  reaction between  sodium  formamide  and  ester 7  is  summarized  in
Figure 3.  The  calculations  depict  a  slightly  exothermic
conversion (ΔG  =  −1.0 kcal•mol−1)  involving  transition
structures of comparable activation energies. Within the small range  of  energies (～1.5  kcal•mol−1),  the  first  acyl  transfer
between  sodium  formamide  and  ester 7        to  give  N-
acylformamide 9 is rate-determining. However, the calculations
are not able to distinguish between the addition of sodium
formamide to ester  7  (TS2) and the elimination of MeOH
from  tetrahedral  intermediate 8        (TS3a)  because  both
transitions states exhibit identical activation energies (ΔG⧧  =
23.2 kcal•mol−1).17  The assistance of a molecule of formamide
in TS3a reduces the activation energy for the C(O)−OMe
bond cleavage relative to the uncatalyzed pathways TS3b and
TS3c,  the  MeOH-mediated  cleavage  TS3d,  and  the  direct
elimination of basic MeONa in TS3e18 (Figure 4). Presumably,
formamide stabilizes the departure of the −OMe leaving group
in a process followed by the barrierless regeneration of sodium
formamide and deprotonation of the resulting N-acylforma-
mide.19 Allred and Hurwitz proposed the nucleophilic attack of
MeONa to the protonated form of N-acylformamide 9 as the
next step in the sequence.3  However, two simple observations
challenge  this  proposal.  First,  the  higher  acidity  of  the
conjugated acid of N-acylformamide 9 relative to formamide
and  MeOH  determines  its  overwhelming  existence  as  the
sodium salt 9.20  Second, the virtually complete deprotonation
of formamide by MeONa results in a negligible concentration
of MeONa. Taken together, these observations suggest the
prevalence of a formyl transfer from sodium N-acylformamide 9
to sodium formamide. The examination of the nucleophilic
attack of sodium formamide to sodium N-acylformamide  9
affords  TS4 along  with  tetrahedral  intermediate 10.  Sub-
sequently, 10 undergoes a 1,3-proton shift to give isomer 11.21
The most stable transition structure (TS5a) for the conversion
of 10 to 11 includes a molecule of MeOH as the proton shuttle
between the two amide nitrogens. Attempts to locate transition
structures corresponding to the participation of formamide as
the proton shuttle (TS5b) or a direct 1,3-proton shift (TS5c)
resulted in structures with lower stabilities possibly due to the
poor ability of formamide to transfer a proton between two
heteroatoms22  and the inadequate geometric arrangement in
the four-membered ring,16  respectively (Figure 4). Tetrahedral
intermediate 11 displays a lengthened N(H)−C(O) bond (1.51
Å relative to isomer  10  (1.45  Å en route to its cleavage
through  TS6.  Finally,  deprotonation  of  formamide  by  the
resulting  sodium  carboxamide 12  is  moderately  favored  to
afford the desired carboxamide 13 and sodium formamide.
The participation of formamide during the departure of the
−OMe  group  in  TS3a  is  seemingly  at  odds  with  the
experimental  zeroth-order  dependence  observed  at  high
formamide concentrations (Figure 2d).23  The existence of the
sodium formamide reactant as a formamide solvate would offer
a plausible explanation for the discrepancy. Indeed, a saturation
behavior for the formation of sodium formamide−formamide
complexes in DMF/MeOH mixtures (eq 5) is in agreement

Figure 4. Alternative transition structures TS3 and TS5. Calculated
activation energies (ΔG⧧, kcal•mol−1) are given in parentheses.
in a process followed by the barrierless regeneration of sodium
formamide and deprotonation of the resulting N-acylforma-
mide.19 Allred and Hurwitz proposed the nucleophilic attack of
MeONa to the protonated form of N-acylformamide 9 as the
next step in the sequence.3  However, two simple observations
challenge  this  proposal.  First,  the  higher  acidity  of  the
conjugated acid of N-acylformamide 9 relative to formamide
and  MeOH  determines  its  overwhelming  existence  as  the
sodium salt 9.20  Second, the virtually complete deprotonation
of formamide by MeONa results in a negligible concentration
of MeONa. Taken together, these observations suggest the
prevalence of a formyl transfer from sodium N-acylformamide 9
to sodium formamide. The examination of the nucleophilic
attack of sodium formamide to sodium N-acylformamide  9
affords  TS4 along  with  tetrahedral  intermediate 10.  Sub-
sequently, 10 undergoes a 1,3-proton shift to give isomer 11.21
The most stable transition structure (TS5a) for the conversion
of 10 to 11 includes a molecule of MeOH as the proton shuttle
between the two amide nitrogens. Attempts to locate transition
structures corresponding to the participation of formamide as
the proton shuttle (TS5b) or a direct 1,3-proton shift (TS5c)
resulted in structures with lower stabilities possibly due to the
poor ability of formamide to transfer a proton between two
heteroatoms22  and the inadequate geometric arrangement in

with reports that indicate a coordinating ability for sodium salts
that follows the order formamide ≥ DMF > MeOH.24  The
persistence of such a complex in transition state TS3a would
concur with the observed first-order in sodium formamide and
zeroth-order in formamide at concentrations higher than 2 M
(eq 6). In contrast, the saturation behavior in MeOH could be
traced to the requirement of sufficient MeOH to facilitate the
1,3-proton shift in TS5a, which in the absence of MeOH would be rate-determining (TS5b or TS5c).
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