On the solvolysis kinetics of amidoesters derived from β-aminoalcohols

Article abstract of DOI:10.1016/j.tetlet.2012.03.017

To better understand reactivity in such systems, fifteen amidoesters derived from β-aminoalcohols were solvolyzed at the ester group in mildly basic methanol-d₄. All trials showed pseudo-first-order kinetics by ¹H NMR. The rate constants are about 2 to 140-fold larger than those found with simple alkyl esters. The least bulky N-acyl groups generally sponsor the largest rate constants, and strongly so in two cases, but apparently not as a result of lesser steric crowding between the amide and ester groups. Rate constants are also greater for those amidoesters favoring an anti conformation at the amide linkage.

Full text of DOI:10.1016/j.tetlet.2012.03.017

Tetrahedron Letters 53 (2012) 2450–2453
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
On the solvolysis kinetics of amidoesters derived from b-aminoalcohols
⇑
Jamilah N. Hankins, Michele Gouws, Amir Mahajer, Ethan S. Kim, Kevin P. Gwaltney, John Haseltine
Department of Chemistry and Biochemistry, Kennesaw State University, Kennesaw, GA 30144, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
To better understand reactivity in such systems, fifteen amidoesters derived from b-aminoalcohols were
solvolyzed at the ester group in mildly basic methanol-d4. All trials showed pseudo-first-order kinetics by
1H NMR. The rate constants are about 2 to 140-fold larger than those found with simple alkyl esters. The
least bulky N-acyl groups generally sponsor the largest rate constants, and strongly so in two cases, but
apparently not as a result of lesser steric crowding between the amide and ester groups. Rate constants
are also greater for those amidoesters favoring an anti conformation at the amide linkage.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 12 July 2010
Revised 1 March 2012
Accepted 5 March 2012
Available online 10 March 2012
Keywords:
Amidoesters
Acyl transfer
Ester solvolysis
Reaction kinetics
Introduction
arrangement occurs in accepted acyl-enzyme intermediates of ser-
ine protease and serine esterase systems.3,4 Some influence should
We reported previously on the base-promoted solvolysis of
N-acyl amino acid esters (Eq. 1; AA = prolyl, N-methylglycyl, or
N-(t-butyl)glycyl; N-acyl = formyl, acetyl, propionyl, isobutyryl, or
trimethylacetyl).1 Some such esters solvolyze unusually easily,
with rate constants up to 100 times greater than those of compa-
rable simple esters. It is also striking that the specific identity of
the N-acyl group can affect the rate constant strongly (Table 1).
We found no evidence of conventional neighboring-group partici-
pation, but we did note the general variation of the rate constant
with the C@O stretching frequency of the N-acyl group. This made
sense if we viewed the NC@O moiety as an electron-withdrawing
group (EWG) and/or a transient charge sink. Any capacity of that
moiety to absorb electron density from the ester group and thus
perhaps enhance ester reactivity would depend on its own specific
electronic character, and NC@O character does plainly vary with
the identity of the N-acyl group, as seen in the IR data.
be expected if the amide group can truly act as an EWG and/or an
electron sink. To address the question in a simple way, we have
carried out the base-promoted methanolysis of fifteen amidoesters
derived from b-aminoalcohols. The measured rate constants do in
fact indicate a general activation as compared with simple alkyl es-
ters. The data also indicate a dependence on structural detail at the
amide linkage.
Results and discussion
Rate constants. Each compound in Figure 1 was converted to its
respective alcohol plus methyl acetate under mild conditions
(0.1 M ester and 1.03 M i-Pr2NEt in methanol-d4, 21.5 1 °C; see
Eq. 2).5,6 The reactions were monitored directly by 1H NMR. The
pseudo-first-order rate constant was calculated from successive
integrations of the diminishing –CH2OAc or CHOAc signal of the
reactant or the growing –CH2OD or CHOD signal of the product.7
The results are given in Table 2.
NꢀAcylꢀAAꢀOEtþMeOD!NꢀAcylꢀAAꢀOMeþEtOD
ð1Þ
We also reported previously on the solvolysis of di- and tripep-
tide esters.2 For such compounds, differences in amide structure
several bonds distant from the ester group had a strong impact
on the ester half-life. In those compounds and in the amino acid
esters, the amide groups are formally part of the acyl portion of
the ester group. In the present work, we wanted to assess whether
an amide group present within an ester’s alkoxy portion would
likewise influence the ester solvolysis kinetics. Such a structural
Table 1
Pseudo-first-order rate constants for formylated, acetylated, and trimethylacetylated
proline esters and ethyl cyclopentane carboxylate undergoing base-promoted meth-
anolysis (0.1 M ester and 1.03 M i-Pr2NEt in methanol-d4 at 21.5 1 °C).1 Ac = acetyl,
Piv = pivaloyl (trimethylacetyl), and Cp = cyclopentyl
Ester
k (10ꢀ5 sꢀ1
)
mNC@O (cmꢀ1
)
OHC-Pro-OEt
Ac-Pro-OEt
Piv-Pro-OEt
CpCO2Et
3.3
1663
1644
1622
—
0.099
0.00053
0.031
⇑
Corresponding author. Tel.: +1 770 499 3426; fax: +1 770 423 6744.
E-mail address: jhaselti@kennesaw.edu (J. Haseltine).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.017

J. N. Hankins et al. / Tetrahedron Letters 53 (2012) 2450–2453
2451
O
Within each amidoester series, the rate constant varies with the
specific identity of the N-acyl group. In general, a smaller N-acyl
group affords higher reactivity. The exception is series 2, with com-
pound 2b yielding a larger rate constant than 2a. The rate constant
is more sensitive to details of structure within series 3 and 4 than it
is within series 1 or 5.
O
1a R = H
2a R = H
AcO
AcO
AcO
AcO
1b R = Me
2b R = Me
N
R
N
R
1c R = t-Bu
CH3
H3C
CH3
CH3
On the basic mechanism of the reaction. In analogy with studies
by Schowen et al. on ester solvolysis, we expected solvolysis under
our conditions to involve a direct, base-assisted pyramidalization
of the ester group by the solvent (Fig. 2, pathway a).8,9 This mech-
anism is consistent with our observed pseudo-first-order kinetics
and with our finding that each amidoester in Figure 1 shows little
or no reactivity when the base is omitted from the reaction. A pos-
sible alternative mechanism involving neighboring-group partici-
pation by the amide group (pathway b) is unlikely for at least
some of the amidoesters. Specifically, amidoesters 5a–c and 6
would require highly strained bridged bicyclic intermediates in
such a mechanism, yet these amidoesters do not in fact exhibit
low reactivity. Furthermore, amidoester 2b should adopt the nec-
essary syn amide geometry for a neighboring-group interaction
only with relative difficulty (vide infra), yet it is more reactive than
its less constrained analog 2a. Barring future evidence to the con-
trary, we will suppose that pathway a is generally valid for the
compounds in this study.
It is noteworthy that 3b, the least reactive amidoester in the
presence of the base, is the most reactive compound when the base
is omitted (k = 7.4 ꢂ 10ꢀ8 sꢀ1). This suggests that 3b may follow an
alternative solvolysis mechanism under neutral conditions. Neigh-
boring-group participation is one possibility.10,11 The structure of
3b is distinctive in having a predominantly syn amide geometry
(vide infra) and containing a geminal dimethyl moiety. By virtue
of a gem-dialkyl effect, it may populate a relatively large propor-
tion of conformations in which a neighboring group interaction is
possible (e.g., syn-3b-II in Fig. 3).12–14
O
O
H3C
CH3
3a R = H
4a R = H
N
R
R
N
R
3b R = Me
4b R = Me
4c R = t-Bu
CH3
O
AcO
CH3
O
5a R = H
N
6
N
5b R = Me
AcO
5c R =
t-Bu
CH3
O
CH3
CH3
AcO
AcO
CH3
AcO
N
8
7
9
CH3
AcO
AcO
CH3
10
11
Figure 1. Amidoesters and alkyl esters used in the present study.
Table 2
Pseudo-first-order rate constants for ester solvolysis, IR stretching frequencies of the
NC@O carbonyl, and 13C NMR chemical shifts of the ester carbonyl
a
Compd
R
k (10ꢀ5 sꢀ1
)
mNC@O (cmꢀ1
)
dOC@O (ppm)b,c
On the nature of the ester activation. In our previous study of the
solvolysis of N-acyl amino acid esters, a dependence of rate con-
stant on the presence and specific identity of the acylamino group
was plainly evident, as is the case here.1 In the previous study, we
interpreted the acylamino moiety as an activating EWG and/or an
electron sink, and the dependence of k on the specific N-acyl group
1a
1b
1c
2a
2b
3a
3b
4a
4b
4c
5a
5b
5c
6
H
4.4
3.5
2.0
2.2
5.6
3.3
0.13
5.5
2.1
0.42
2.7
2.5
2.1
3.8
1663
1639
1625
1651
1645
1647
1640
1658
1636
1619
1653
1630
1602
1672
1677
—
170.7, 170.8
170.7, 170.8
170.8
170.8, 171.0
170.8
170.6, 170.8
170.9
170.6, 170.9
170.5, 170.7
171.1
170.4, 170.6
170.4, 170.6
170.6
170.8
171.0
Me
t-Bu
H
Me
H
Me
H
Me
t-Bu
H
Me
t-Bu
—
—
—
pathway
a
O
O
OCD3
H3C O
H3C
O
N
R
N
R
O
7
8
9
10
11
1.9
O
CH3
O
CH3
0.27
0.023
0.23
0.086
171.3
171.5
171.5
171.2
—
—
—
—
—
—
pathway
b
a
b
c
Obtained for neat compounds.
Obtained for CDCl3 solutions.
Values are given for both amide conformations, syn and anti, if observed.
O
DO
H3C
O
N
R
O
+
CH3
products
R
H3C
OCD3
N
CH3
O
ROAc þ MeOD ! ROD þ MeOAc
ð2Þ
The results show the amidoesters to be generally activated in
comparison to simple alkyl esters. For example, amidoesters 1a–c
are about 7 to 16-fold more reactive than ethyl acetate (8).
Likewise, amidoesters 5a–c are 24 to 31-fold more reactive than
cyclopentyl acetate (11). Amidoester 3a shows an unusually large
degree of activation compared to a sterically similar alkyl analog
(neopentyl acetate, 9; k3a ꢁ 140 ꢂ k9). Only 4c shows a relatively
small activation compared to an alkyl analog (isobutyl acetate,
10; k4c ꢁ 1.7 ꢂ k10).
attack
by
O
O
R
D3CO
O
solvent
O
CH3
CH3
DO
DO
N
R
N
CH3
CH3
Figure 2. Simple pathways for base-promoted solvolysis of amidoesters from
Figure 1.

2452
J. N. Hankins et al. / Tetrahedron Letters 53 (2012) 2450–2453
ric interactions within compounds 2a and 3b were expected, a pri-
H3C
O
CH3
O
ori, to favor the syn conformation, while steric interactions within
2b and 3a were expected to favor anti (Fig. 5). The simple CDCl3
and CD3OD NMR spectra are consistent with these expectations.
For example, the 1H spectra of all other N-formyl and N-acetyl
compounds in the study show two sets of signals each, correspond-
ing to syn and anti conformations. The spectra for 2b and 3b, how-
ever, each show a single set of signals at temperatures as low as
ꢀ77 °C. The spectra for 2a and 3a each show two sets of signals
at 21 °C. By integration of the 1H signals, the population ratio of
conformations in 3a is 20:1. The ratio in 2a is solvent-dependent,
being about 26:1 in CDCl3 and about 18:1 in CD3OD, but favoring
the same conformation in each solvent. Comparison of the 13C
spectra for 2a versus 2b suggests that the sole amide conformation
in 2b is the minor conformation in 2a, as expected. In particular,
the N-CH2 carbon in 2a shows 13C resonances at 44.93 ppm (minor
conformer) and 39.99 ppm (major conformer), while the corre-
sponding carbon in 2b shows a resonance at 44.39 ppm only. Com-
parison of the13 C spectra of 3a versus 3b likewise suggests that the
sole amide conformation in 3b is the minor conformation in 3a, as
expected. In particular, the N-Me carbon in 3a shows resonances at
33.75 ppm (minor conformer) and 26.26 ppm (major conformer),
while the corresponding carbon in 3b shows a resonance at
34.06 ppm only. All of these observations are consistent with an
assignment of syn-2a, anti-2b, anti-3a, and syn-3b as the most sta-
ble conformations in their respective ground-state conformational
equilibria.
O
O
O
O
H3C
H3C
H3C
H3C
N
N
CH3
CH3
CH3
CH3
syn-3b-I
syn-3b-II
Figure 3. A gem-dimethyl effect in 3b should enhance the proportion of confor-
mations that have the ester and amide groups close to one another, for example,
syn-3b-II.
as the result of differences in the various acylamino groups’ elec-
tron-withdrawing capacities. The IR stretching frequency of the
N-acylcarbonyl group was noted to generally decrease as the bulk
of the N-acyl group was increased (Table 1). This observation sug-
gested that variations in local crowding by the N-acyl group (e.g.,
Fig. 4) affect the electronic character of the N–C@O moiety and,
in turn, its capacity as an EWG or sink.
To assess whether the acylamino group in the present study
acts as an EWG, the 13C shift of the ester carbonyl was examined.
Maciel et al. found that in esters of structure AcOCH2CH2X, typical
EWGs (X = Br, Cl, Ph, OCH3, and NMe3+) deshield the C@O carbon
by 0.1–0.8 ppm relative to that of ethyl or propyl acetate.15,16
The acylamino group in the present study, however, has a mild
shielding effect on the ester carbonyl. The ester C@O signal for each
amidoester, 1–7, falls between 170.4 and 171.1 ppm while that for
the alkyl esters 8–11 falls between 171.2 and 171.5 ppm (Table 2).
Thus while ground-state electron-withdrawing character for the
acylamino group cannot be ruled out on this simple basis, the
13C data do not seem to indicate such character.
Now, if anti and syn amide conformations activate the ester
group to different degrees, and if anti were generally more activat-
ing than syn, then the greater reactivity of 2b compared to 2a can
be explained. That is, the intrinsic steric bias in 2b favors a more
reactive conformation. Such a conformational factor would be
superimposed on the crowding factor proposed above that would
Does the specific identity of the N-acyl group affect the elec-
tronic character of the N–C@O moiety? A dependence is clearly
evident in Table 2. Within each set of compounds, 1 through 5,
as the bulk of the N-acyl group is increased, the stretching fre-
O
H
AcO
AcO
quency of the N–C@O carbonyl decreases by as much as 51 cmꢀ1
.
N
H
N
O
At the same time, the value of k also decreases (except for ester
2b). Therefore, if the acylamino and ester groups interact electron-
ically in some fashion, as seems inevitable from their mutual prox-
imity, the N-acyl group may be influencing ester reactivity through
an impact on N–C@O character. We currently suppose that the de-
gree of such impact depends on the specific degree of crowding
within each amide group, as we argued previously for the amino
acid esters.1
H3C
CH3
CH3
H3C
CH3
CH3
syn-2a
anti-2a
O
CH3
O
AcO
AcO
N
CH3
N
On the influence of amide conformation. Table 2 shows that with-
in each of the amidoester series 1, 3, 4, and 5, bulkier N-acyl groups
always afford lower values of k. The reactivity of 3b is conspicuous
within this trend since it is particularly low as compared with its
analog 3a. It is also conspicuous that amidoesters 2a and 2b do
not fit the general trend since 2b is more reactive than 2a. Both
of these results make sense if we infer a dependence of ester reac-
tivity on amide conformation as follows.
H3C
CH3
CH3
H3C
CH3
CH3
syn-2b
anti-2b
H3C
H3C
H3C
H3C
O
H
AcO
AcO
AcO
AcO
N
H
N
O
Each of the compounds in sets 1–5 can in principle populate
two different conformations at the amide linkage, syn and anti. Ste-
CH3
CH3
syn-3a
anti-3a
O
H3C
H3C
H3C
H3C
O
CH3
R = H, Me, Et
-Pr, or -Bu
OEt
R
N
i
t
N
CH3
N
O
O
CH3
CH3
syn-3b
anti-3b
Figure 4. Crowding within the amide group of N-acyl amino acid esters that
correlates with the IR stretching frequency of the N-acyl carbonyl (from Ref. 1).
Larger R groups sponsor a lower frequency and a lower rate constant for solvolysis
at the ester group.
Figure 5. Differential steric interactions that favor the syn amide conformation in
compounds 2a and 3b and the anti amide conformation in 2b and 3a.

J. N. Hankins et al. / Tetrahedron Letters 53 (2012) 2450–2453
2453
tend to make 2b less reactive than 2a. If these two factors truly
operate as the main determinants of relative reactivity, the confor-
mational factor must outweigh the crowding factor in these two
compounds since 2b is in fact more reactive than 2a.
The especially low reactivity of 3b also makes sense by this
model since the crowding and conformational factors should both
act to depress reactivity in 3b. That is, 3b has greater crowding in
its amide group than 3a, and the intrinsic steric bias in 3b favors a
less reactive (syn) conformation.
Esters 2a, 2b, 3a, and 3b were selected for this study to test for a
conformational factor after such a factor became evident in our
amino acid study.1 As a further test in the present context, lac-
tam-esters 6 and 7 were also prepared and solvolyzed. The lactam
rings in these two compounds lock the amide moiety into anti and
syn conformations, respectively. The observation that 6 is indeed
more reactive than 7 (Table 2) lends further support to the idea
that the anti conformation is more activating.
It is an open question as to how amide conformation is able to
influence the solvolytic reactivity of the present compounds, as is
the question of whether that influence is actually separate from
the fundamental mechanism of ester activation. Further studies
are in progress.
Acknowledgment
We are grateful to the College of Science and Mathematics of
Kennesaw State University for support of this work.
References and notes
1. Haseltine, J.; Runyon, J. W. Tetrahedron Lett. 2010, 51, 3280.
2. Fan, Y.-H.; Grégoire, C.-A.; Haseltine, J. Bioorg. Med. Chem. 2004, 12, 3097.
3. Hedstrom, L. Chem. Rev. 2002, 102, 4501.
4. Sutton, L. D.; Stout, J. S.; Quinn, D. M. J. Am. Chem. Soc. 1990, 112, 8398.
5. Except for 6 and 7, all amidoesters in Figure
1 were prepared from the
corresponding aminoalcohols by bis-acetylation or by sequential N-acylation
and O-acetylation. Lactam-esters 6 and 7 were prepared by acetylation of the
corresponding lactam-alcohols, which were prepared by reduction of the
corresponding ethyl esters with NaBH4/MeOH.1
Conclusion
6. Each amidoester in Figure 1 gave satisfactory 1H NMR, 13C NMR, IR, and high-
resolution mass spectral data.
The amidoesters used in this study are generally activated for
base-promoted solvolysis in comparison to simple alkyl esters. In
most cases, the smallest N-acyl groups afford the greatest degrees
of activation. Within each of the series 1–5, the IR stretching fre-
quency of the NC@O carbonyl decreases as the size of the N-acyl
group is increased (Table 2). This impact is likely due to greater
crowding within the bulkier amide groups, as we discussed in de-
tail in our previous paper.1 Because the amide and ester groups in
these molecules are intimate neighbors, this impact on NC@O
character is suspected to be a direct factor behind the measured
solvolysis rate constants. For example, NC@O may serve as an
inductive or hyperconjugative electron sink during ester solvolysis,
and its precise capacity to do so may be modulated by the identity
of its N-acyl group. Finally, three of the pairs of amidoesters in this
study were used to gauge the impact of amide conformation on es-
ter reactivity. The results with all three pairs indicate that an anti
conformation is more activating than syn.
7. For each kinetics trial, 1.00 mL of a 1.03 M (i-Pr)2NEt/MeOH-d4 solution was
added to a measured amount of ester so that the initial concentration of ester
was about 0.1 M. Kinetics data were collected as a series of signal integrations
with a Bruker Avance DPX-300 NMR spectrometer. Each rate constant was
calculated by the least-squares method for the simple linear regression
equation ln (%ROAc) = ꢀkt + C. Each value in Table 2 is the average of at least
two determinations.
8. Mitton, C. G.; Schowen, R. L.; Gresser, M.; Shapley, J. J. Am. Chem. Soc. 1969, 91,
2036.
9. Mitton, C. G.; Gresser, M.; Schowen, R. L. J. Am. Chem. Soc. 1969, 91, 2045.
10. Capon, B. Quart. Rev. 1964, 18, 45.
11. Bowden, K. Adv. Phys. Org. Chem. 1993, 28, 171.
12. Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. J. Chem. Soc. Trans. 1915, 1080.
13. Jung, M. E.; Gervay, J. J. Am. Chem. Soc. 1991, 113, 224.
14. Bachrach, S. M. J. Org. Chem. 2008, 73, 2466.
15. Maciel, G. E.; Simeral, L.; Elliott, R. L.; Kaufman, B.; Cribley, K. J. Phys. Chem.
1972, 76, 1466.
16. Simeral, L.; Maciel, G. E. J. Phys. Chem. 1973, 77, 1590.