Guanidine-guanidinium cooperation in bifunctional artificial phosphodiesterases based on diphenylmethane spacers; Gem -dialkyl effect on catalytic efficiency

Article abstract of DOI:10.1021/jo401085z

Diphenylmethane derivatives 1-3, decorated with two guanidine units, are effective catalysts of HPNP transesterification. Substitution of the methylene group of the parent diphenylmethane spacer with cyclohexylidene and adamantylidene moieties enhances catalytic efficency, with gem-dialkyl effect accelerations of 4.5 and 9.1, respectively. Activation parameters and DFT calculations of the rotational barriers around the C-Ar bonds indicate that a major contribution to the driving force for enhanced catalysis is entropic in nature.

Full text of DOI:10.1021/jo401085z

Note
pubs.acs.org/joc
Guanidine−Guanidinium Cooperation in Bifunctional Artificial
Phosphodiesterases Based on Diphenylmethane Spacers; gem-
Dialkyl Effect on Catalytic Efficiency
Riccardo Salvio,* Luigi Mandolini, and Claudia Savelli
Dipartimento di Chimica and IMC-CNR Sezione Meccanismi di Reazione, Universita
Italy.
̀
La Sapienza, P.le Aldo Moro 5, 00185 Roma,
S
* Supporting Information
ABSTRACT: Diphenylmethane derivatives 1−3, decorated with two
guanidine units, are effective catalysts of HPNP transesterification.
Substitution of the methylene group of the parent diphenylmethane
spacer with cyclohexylidene and adamantylidene moieties enhances
catalytic efficency, with gem-dialkyl effect accelerations of 4.5 and 9.1,
respectively. Activation parameters and DFT calculations of the
rotational barriers around the C−Ar bonds indicate that a major
contribution to the driving force for enhanced catalysis is entropic in
nature.
n the past two decades simple, nonpeptidic molecules that
Imimic structural and functional aspects of natural enzymes
have received considerable attention.1,2 The extreme reluctance
of phosphodiester bonds to undergo hydrolytic cleavage has
challenged many research groups to design and synthesize
artificial catalysts capable of cleaving DNA, RNA, and their
model compounds.3−6
cyclohexylidene or adamantylidene moieties as a manifestation
of the gem-dialkyl effect7,8 in supramolecular catalysis.
In the majority of cases, these artificial catalysts contain metal
cations as catalytically active components, notably copper(II)
and zinc(II).3,4g Less numerous are examples of catalysts devoid
of metal centers.3e,4−6 In a recent study,6 the high catalytic
efficiency of diguanidinocalix[4]arenes in the transesterification
of 2-hydroxypropyl p-nitrophenyl phosphate (HPNP) was
reported. It was shown that a necessary requisite for catalysis is
the simultaneous presence, on the same molecular framework,
of a neutral guanidine acting as a general base and a protonated
guanidine acting as an electrophilic activator. In these
bifunctional catalysts, as in many other catalysts of the same
kind, an important role is played by the molecular scaffold
connecting the catalytic groups. An efficient scaffold should
keep the active functions at the proper distance as a result of a
good compromise between preorganization and flexibility.
Flexibility ensures good adaptability of the bifunctional catalyst
to the altered substrate in the transition state, but the resulting
entropic cost may greatly reduce catalytic efficiency.
With these ideas in mind, we have synthesized and
investigated the catalytic activity of bifunctional catalysts 1−3
in the transesterification of HPNP (eq 1). Here we show that
the efficiency of bifunctional catalysts based on diphenyl-
methane spacers is comparable to those of the more structurally
elaborated cone 1,2- and 1,3-diguanidinocalix[4]arenes.6 We
also show that catalytic activity can be significantly improved
when the methylene group in 1 is replaced by bulkier
Guanidinylation of the appropriate 4,4′-diaminodiphenyl
derivative 4 was carried out with bis-Boc-thiourea and HgCl2,
followed by deprotection with hydrochloric acid in dioxane
(Scheme 1). Whereas 4,4′-diaminodiphenylmethane (4a) was
comercially available, the required cyclohexane and adamantane
derivatives (4b9 and 4c,10 respectively) were prepared
according to slightly modified literature procedures.
Received: March 22, 2013
© XXXX American Chemical Society
A
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The Journal of Organic Chemistry
Note
a
Scheme 1. Synthesis of Diguanidinylated Diphenylmethanes 1−3
a
Reagents and conditions: (a) BocNHC(S)NHBoc, HgCl2, Et3N, DMF; (b) 0.5 M HCl, 1,4-dioxane.
Determination of acidity constants of 1(H+)2−3(H+)2 is a
prerequisite for a meaningful investigation of their catalytic
properties. A mixture of DMSO/H2O 80:20 (v/v), hereafter
referred to as 80% DMSO, was used as reaction medium in
titration experiments. This mixture is well-known to be suitable
for potentiometric measurements and for investigation of
hydrolytic reactions of phosphodiesters3o,5,6 and for dephos-
phorylation of ATP to ADP.11 The pKw for water
autoprotolysis in 80% DMSO rises to 18.4,12 and this implies
that the pH value of a neutral solution is 9.2.
The chloride salts of diprotonated bases (2.0 mM) were
potentiometrically titrated with a standard solution of
Figure 1. Plot of pseudo-first-order rate constants kobs for the
liberation of p-nitrophenol from 0.10 mM HPNP (80% DMSO, 25 °C,
10 mM Me4NClO4) catalyzed by 1−3 in 80% DMSO versus total
catalyst concentration. The second-order rate constants k2 in Table 1
were calculated from the slopes of the straight lines.
Me4NOH in 80% DMSO in the presence of 10 mM
Me4NClO4. Analysis of the titration plots (Figures S1−S3 in
Supporting Information) afforded the pK values listed in Table
1.
Table 1. Acidity Constants of Hydrochlorides of 1−3 in 80%
Table 2. Kinetic Parameters for the Transesterification of
HPNP Catalyzed by 1−3 in 80% DMSO, 25°C
a
DMSO, 25 °C
a
pK1
pK2
b
c
d
e
102 × k2 (s−1 M−1
)
102 × kcat (s−1 M−1
)
krel
EM (M)
1·2HCl
2·2HCl
3·2HCl
9.13 0.08
8.92 0.07
8.78 0.06
11.62 0.08
11.54 0.07
11.51 0.08
1·2HCl
2·2HCl
3·2HCl
0.42 0.02
1.91 0.06
4.04 0.12
0.45 0.03
2.04 0.06
4.09 0.08
1
0.45
2.0
4.5
9.1
4.1
a
pKi data from potentiometric titrations carried out on 2.0 mM
substrate solutions in the presence of 10 mM Me4NClO4. Reported
errors are standard deviations σ.
a
2.0 mM precatalyst, 10 mM Me4NClO4, reported errors are standard
b
deviations σ. Calculated from the slopes of the straight lines in Figure
c
d
1H+
1. From best fit to eq 2 of rate data in Figure 2. krel = kcat /kcat
.
e
EM = kcat/kinter, calculated using kinter = (1.0 0.2) × 10−2 M−2 s−1
from ref 6.
The catalytic activity of compounds 1−3 in the trans-
esterification of HPNP was investigated under the same
conditions used for the potentiometric titrations, namely,
80% DMSO containing 10 mM Me4ClO4 at 25.0 °C. In a first
set of rate measurements, solutions of diprotonated catalysts
were half-neutralized with 1 molar equiv of Me4NOH. The
resulting buffer solutions, in which the predominant species is
the monoprotonated form of the catalyst, were used for the
transesterification of HPNP. The results of the kinetic
experiments are graphically shown in Figure 1 as plots of
pseudo-first-order rate constants (kobs, s−1) for the spectropho-
tometrically determined liberation of p-nitrophenol versus total
catalyst concentration (Ccat). Data points could be fitted in all
cases to straight lines with zero intercept, showing that (i) the
catalyst works under subsaturating conditions, i.e., binding of
HPNP to the catalyst is in all cases too low to affect the kinetics
in the investigated concentation range, and (ii) contributions
from background hydrolysis to the overall rate are, as
expected,13 negligibly small.
diprotonated catalyst with calculated amounts of Me4NOH
afforded a number of buffer solutions with pH values in the
range of around 8−12, which were used for catalytic rate
measurements. Pseudo-first-order rate constants (kobs) for the
transesterification of HPNP, corrected for background
contributions13 whenever appropriate (pH > 11), are shown
in Figure 2. The bell-shaped pH−rate profiles could be fitted to
a good precision to eq 2, based on the assumption that the
monoprotonated forms of the catalysts (cat·H+) are the only
catalytically active species (eq 3).
kcatC
cat
kobs
=
[H+]
K2
[H+]
+
+ 1
K1
(2)
(3)
v = kcat[catH+][HPNP]
In eq 2, K1 and K2 are the known acidity constants from
Table 1, while kcat is the only adjustable parameter in a
nonlinear least-squares fitting procedure. The best fit kcat values,
listed in Table 2, compare well with the corresponding k2
values, calculated as the slopes of the straight lines in Figure 1.15
To sum up, the kinetics fully confirm that compounds 1−3 are
The slopes of the straight lines are second -order rate
constants (k2, Table 2) based on the total catalyst
concentration (Ccat).14 In a second set of kinetic experiments,
the catalytic efficiency was systematically investigated over a
wide pH range. Partial neutralization of 2.0 mM solutions of
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The Journal of Organic Chemistry
Note
(more favorable) than that of the unsubstituted parent
compound, as a consequence of steric hindrance to internal
rotation caused by bulky substituents.19
To shed light on the origin of rate enhancement caused by
bulky substituents, the temperature dependence of catalytic
rates was investigated in the temperature range 25−55 °C.
Analysis of rate data according to the Eyring equation afforded
the activation parameters listed in Table 3 (see Supporting
Table 3. Activation Parameters for the Transesterification of
a
HPNP Catalyzed by 1−3
b
ΔG⧧ (kcal mol−1
)
ΔH⧧ (kcal mol−1
)
ΔS⧧ (cal K−1 mol−1
)
1H+
2H+
3H+
20.65 0.05
19.80 0.03
19.35 0.03
19.3 0.5
19.6 0.4
−4.6 1.5
−0.5 1.2
4.5 2.0
Figure 2. pH−rate profiles for the cleavage of 0.10 mM HPNP
catalyzed by 2.0 mM 1−3 in 80% DMSO, 25.0 °C, 10 mM
Me4NClO4. The rate constants measured at pH > 11 were corrected
for background hydrolysis (kbg = 10(pH−17.2), see ref 6).
20.7 0.6
a
b
See Supporting Information for details. At 25 °C.
Information for details). Whereas the enthalpy of activation of
the reaction of 1H+ and 2H+ are virtually identical, the
corresponding value of the reaction of the adamantane
derivative 3H+ is slightly larger, but the range of ΔH⧧, 1.4
kcal mol−1, is only slightly larger than the sum of statistical
errors, 1.1 kcal mol−1. Since the possibility of nonrandom errors
cannot be ruled out, it is difficult to say whether the slightly
larger value of the adamantane derivative is a real phenomenon,
or an experimental artifact. A different situation is observed
with the entropy of activation.20 Here the observed range of
ΔS⧧, 9.1 cal K−1 mol−1, is decidedly larger than the sum of
statistical errors, 3.5 cal K−1 mol−1. It appears therefore that
there is an undeniable tendency for ΔS⧧ to become less
negative (more favorable) when the catalytic efficiency
increases in the order of 1H+ < 2H+ < 3H+. In other words
the activation parameters indicate that the origin of rate
enhancements caused by alkyl substituents is essentially
entropic in nature.
catalytically active only in their monoprotonated forms, in
agreement with previous conclusions6 that bifunctional catalysis
arises from the combined action of a neutral guanidine acting as
a general base and a protonated guanidine acting as a general
acid, as schematically depicted in Figure 3.
Figure 3. Suggested mechanism of HPNP cleavage catalyzed by 1H+−
3H+.
This view was strongly corroborated by DFT calculations
carried out on simple model compounds with Gaussian 03
package21 at the B3LYP 6-31g(d) level of theory. As shown in
Table 4 an increase in steric bulk causes a marked increase in
Catalytic rate constants and EM values (Table 2) are very
similar to those reported for the 1,3- and 1,2-
diguanidinocalix[4]arenes under the same conditions,6 namely,
kcat = 2.3 × 10−2 M−1 s−1 (EM = 2.3 M) and kcat = 1.1 × 10−2
M−1 s−1 (EM = 1.1 M), respectively, showing that even 1H+,
despite its structural simplicity, can achieve high levels of
catalytic efficiency in the cleavage of HPNP. Bulky substituents
enhance the catalytic activity to a significant extent, the
adamantane derivative 3H+ being nearly an order of magnitude
more effective than the parent compound 1H+.
It has long been known that alkyl substituents frequently
enhance rates and equilibria of processes involving the closing
of rings from their noncyclic precursors. For historical reasons
the effect is called the “gem-dimethyl (-dialkyl) effect” or
Thorpe−Ingold effect.7,8,16 Earlier explanations focused on the
formation of small rings, in which the diminution of the internal
angle would lead to a spreading apart of the external angle.16 An
additional, more general explanation was put forward by
Hammond in terms of restriction of internal rotation caused by
alkyl substituents in open chain compounds.17 Good grounds
for supporting Hammond’s suggestion were provided a few
years later by Allinger and Zalkow in quantitative terms.18
Analysis of available quantitative data on the hypothetical gas-
phase cyclization reactions of alkyl-substituted hexanes to
cyclohexanes showed the entropy of formation of alkyl-
substituted ring compounds to be in all cases less negative
a
Table 4. Barrier Height (Vo) for the Rotation around the
b
C−Ar Bonds and Corresponding Contribution to the
c
Entropy of Internal Rotation in Model Compounds
Vo
Sconf per rotor
S°conf
model compound
diphenylmethane
(kcal mol−1
)
(cal K−1 mol−1
)
(cal K−1 mol−1
)
0.53
7.6
5.5
15.2
12.6
1,1-
5.65 (ax)
diphenylcyclohexane
1.42 (eq)
9.88
7.1
4.9
2,2-
9.8
diphenyladamantane
a
b
Calculated by B3LYP 6-31g(d) DFT methods. Calculated using
c
Pitzer treatment of internal rotations. See Supporting Informations
for details.
the height of the rotational barrier around the C−Ar bonds and
hence a significant reduction of the entropy of internal rotation
S°conf. Although too much emphasis cannot be placed on exact
figures, comparison with ΔS⧧ data (Table 3) shows that the
driving force for enhanced catalysis of 2H+ and 3H+ relative to
1H+ is well commensurate to the reduction of conformational
entropy caused by steric hindrance in the reactant state.
C
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Note
1,1-Bis[4-guanidinephenyl)cyclohexane Bis-hydrochloride
(2·HCl). A solution of compound 5b (210 mg, 0.280 mmol) in 15
mL of a 1:1 mixture of dioxane and 0.5 M hydrochloric acid was stirred
for 2 days at room temperature. Evaporation of the solvent gave
compound 2·2HCl as a colorless glassy solid (115 mg, 0.272 mmol,
97% yield). 1H NMR (300 MHz, D2O): δ 7.45 (d, 4H, J = 9 Hz), 7.18
(d, 4H, J = 9 Hz), 2.28 (m, 4 H), 1.49 (m, 6H). 13C NMR (75 MHz,
D2O): δ 156.9 132.2 129.2 126.5 132.5 46.1 36.7 26.3 23.1 HR ES-
MS: m/z calcd for C20H28N6Cl+ [M + 2H + Cl]+ 387.2064, found
387.2067.
2,2-Bis(4-aminophenyl)adamantane (4c). Aniline hydrochlor-
ide (5.1 g, 39 mmol) was added to a solution of 2-adamantanone (2.0
g 13 mmol) in 7 mL of aniline, and the mixture was stirred at 160 °C
for 60 h. After cooling, the solution was made basic with aqueous
NaOH, and the oily layer was separated and distilled under vacuum to
remove unreacted aniline. The crude product was treated with active
carbon to remove the dark color and chromatographed (SiO2, hexane/
AcOEt from 10:1 to 3:1). Compound 4c, obtained as a pale yellow
solid (1.78 g, 18.4 mmol, 43% yield), showed the same spectroscopic
properties as those reported in the literature.10
In conclusion, the data reported in this work show that
compounds 1H+−3H+ are effective catalysts of HPNP
transesterification. EM values of 0.45−4.0 M indicate a high
degree of synergism22 displayed by neutral and protonated
guanidinium units of the bifunctional catalyst in the
stabilization of the transition state. The catalytic advantage of
the diphenylcyclohexane and diphenyladamantane derivatives
over the parent diphenylmethane compound provides, to the
best of our knowledge, the first example of the operation of the
gem-dialkyl effect in supramolecular catalysis as a means of fine-
tuning catalytic activity. Activation parameters and DFT
calculations suggest that this effect is an essentially entropic
phenomenon, in that the bulky cyclohexane and adamantane
moieties significantly reduce the conformational mobility
around the C−Ar bonds and, consequently, the cost in entropy
required to reach the transition state, without reducing the
adaptability of the catalyst to the altered HPNP substrate in the
transition state.
2,2-Bis[4-(N,N′-di(tert-butoxycarbonyl)guanidinephenyl)-
adamantane (5c). The reaction was carried out according to the
same procedure used for the preparation of compound 5a, starting
from compound 4c (210 mg, 0.66 mmol) and 2 molar equiv of bis-
Boc-thiourea. A pure sample of 5c was obtained by flash column
chromatography (SiO2, hexane/AcOEt 20:1) as a colorless oil (517
EXPERIMENTAL SECTION
■
Instruments and General Methods. NMR spectra were
recorded on a 300-MHz spectrometer. Chemical shifts are reported
as δ values in ppm from tetramethylsilane added as an internal
standard. Mass spectra were performed by an electrospray ionization
time-of-flight spectrometer.
1
mg, 46% yield). H NMR (300 MHz, CDCl3): δ 11.60 (br s, 2H),
10.19 (br s, 2H), 7.45 (d, 9 Hz, 4H), 7.32 (d, 9 Hz, 4H), 3.18 (s, 2H),
2.09−1.97 (m, 4H), 1.83−1.65 (m, 8H), 1.50 (s, 18H), 1.48 (s, 18H).
13C NMR (75 MHz, CDCl3): δ 163.5 153.3 153.2 144.9 133.5 126.2
122.1 83.5 79.5 50.0 37.9 33.2 31.9 28.1 28.0 27.4 HR ES-MS: m/z
Materials. DMSO purged 30 min with argon and mQ water were
used in the preparation of 80% DMSO. HPNP was prepared as
reported in the literature.23 Other solvents and reagents were
commercially available and used without any further purification.
4,4′-Bis[N,N′-di(tert-butoxycarbonyl)guanidine]diphenyl-
methane (5a). A stirring solution of 4,4′-diaminodiphenylmethane
(495 mg, 2.50 mmol) and bis-Boc-thiourea (1.40 g, 5.07 mmol) in 6
mL of dry DMF (Aldrich, 99.8%) was cooled to 0 °C with an ice bath,
and then Et3N (1.75 mL, 12.6 mmol) and HgCl2 (1.36 g, 5.04 mmol)
were added. After 2 h, the reaction was quenched by adding AcOEt
(30 mL), and the HgS precipitate was filtered. The solvent was
removed, and the residue chromatographed (SiO2, hexane/AcOEt
10:1). Compound 5a, obtained as a white solid (648 mg 0.950 mmol,
38% yield), showed the same spectroscopic properties as those
reported in the literature.24
+
calcd for C44H63N6O8 [M + H]+ 803.4707, found 803.4720.
1,1-Bis[4-guanidinephenyl)adamantane Bis-hydrochloride
(3·HCl). The reaction was carried out according to the same
procedure used for the preparation of compound 1 starting from
compound 5c (300 mg 0.280 mmol). Compound 3·2HCl was
obtained as a colorless colorless glassy solid (115 mg, 0.272 mmol,
97% yield). 1H NMR (300 MHz, D2O): δ 7.55 (d, 9 Hz, 4H), 7.16 (d,
9 Hz, 4H), 3.28 (s, 2H), 1.95−1.55 (m, 8H). δ156.1 148.1 131.2 127.4
+
126.1 50.6 37.4 32.8 31.3 27.1 HR ES-MS: m/z calcd for C24H31N6
[M + H]+ 403.2610, found 403.2615; m/z calcd for C24H32N6+2 (M +
2H+) 202.1344, found 202.1346.
4,4′-Diguanidinediphenylmethane Bis-hydrochloride
(1·2HCl). A solution of compound 5a (180 mg, 0.264 mmol) in 15
mL of a 1:1 mixture of dioxane and 0.5 M hydrochloric acid was stirred
for 2 days at room temperature. Evaporation of the solvent gave
compound 1·2HCl as a white solid (89 mg, 0.251 mmol, 95% yield)
that showed the same spectroscopic properties as those reported in the
literature.24
Potentiometric Titrations. Potentiometric titrations were
performed by an automatic titrator equipped with a combined
microglass pH electrode. Experimental details and procedure for the
electrode calibration were the same as previously reported.6
Potentiometric titrations were carried out under a nitrogen
atmosphere, on 6 mL of 2 mM solutions of the compound, in the
presence of 10 mM Me4NClO4, (80% DMSO, 25 °C). A 50 mM
Me4NOH solution in 80% DMSO was added to the titration vessel in
small increments. Analysis of titration plots was carried out by the
program HYPERQUAD 2000.25
Kinetic Measurements. Kinetic measurements of HPNP trans-
esterification were carried out by UV−vis monitoring of p-nitrophenol
liberation at 400 nm on either a double beam or on a diode array
spectrophotometer. Rate constants were obtained by an initial rate
method, error limits on the order of 5%. A typical kinetic run is
reported in Supporting Information.
Theoretical Calculations. DFT calculations were carried out at
the B3LYP/6-31G(d)//B3LYP/6-31G(d) level of theory (GAUS-
SIAN-03 package). Barriers for the rotation around the C−Ar bonds
were determined by difference of the energies, corrected for the zero-
point vibrational energy, of the ground state and transition state
(opt=ts keyword) for the rotation. Vibrational analysis confirmed all
stationary points to be minima (no imaginary frequencies) or first-
order saddle points (one imaginary frequency) in the case of transition
states of the rotation. The contributions of the internal rotation to
entropy were calculated using Pitzer treatment.26 Further details are
reported in Supporting Information.
1,1-Bis(4-aminophenyl)cyclohexane (4b). Excess aniline (10
mL, 110 mmol) was added to a solution of cyclohexanone (3.0 g, 30.6
mmol) in 11 mL of 35% hydrochloric acid, and the mixture was stirred
at 150 °C for 48 h. After cooling, the solution was made basic with
aqueous NaOH to pH 13, and the oily layer was separated and distilled
to remove unreacted aniline. The residue was chromatographed (SiO2,
hexane/AcOEt from 10:1 to 3:1), and compound 4b, obtained as a
pale yellow solid (4.91 g, 18.4 mmol, 60% yield), showed the same
spectroscopic properties as those reported in the literature.9
1,1-Bis[4-(N,N′-di(tert-butoxycarbonyl)guanidinephenyl)-
cyclohexane (5b). The reaction was carried out according to the
same procedure used for the preparation of compound 5a, starting
from compound 4b (310 mg, 1.16 mmol) and 2 molar equiv of bis-
Boc-thiourea. A pure sample of 5b was obtained by flash column
chromatography (SiO2, hexane/AcOEt 10:1) as a colorless oil (455
1
mg, 52% yield). H NMR (300 MHz, CDCl3): δ 11.63 (br s, 2 H),
10.25 (br s, 2 H), 7.49 (d, 4H, J = 9 Hz), 7.21 (d, 4H, J = 9 Hz), 2.22
(m, 4 H), 1.50 (m, 6H), 1.51 (d, 36 H, J = 9 Hz). 13C NMR (75 MHz,
CDCl3): δ 153.4 153.2 145.0 134.0 127.7 121.8 83.6 77.4 45.7 37.1
28.1 28.0 26.3 22.8 14.1. HR ES-MS m/z: [M + H]+ calcd for
+
C40H59N6O8 751.4394; found 751.4378.
D
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The Journal of Organic Chemistry
Note
(12) Kreevoy, M. M.; Baughman, E. H. J. Phys. Chem. 1974, 78, 421.
(13) Rate constants for the background hydrolysis of HPNP are
available from a previous investigation, kbg = 10pH‑7.20 from ref 6. From
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra, details of the DFT calculations, plots
of potentiometric acid−base titrations, and a typical kinetic run.
This material is available free of charge via the Internet at
http://pubs.acs.org.
this equation we calculate kbg = 0.95 × 10−7 s−1 at pH 10.16 and kbg
=
1.60 × 10−7 s−1 at pH 10.39. These values show that in the given pH
range background contributions to the liberation of p-nitrophenol are
2 to 3 orders of magnitude lower than catalytic rates.
(14) As noted by a reviewer, the acceleration effect of alkyl
substituents is somewhat larger than actually measured, because the
basicity of the guanidine moiety acting as a general base decreases in
the order 1 > 2 > 3. Combination of ΔpK1 values of hydrochlorides of
AUTHOR INFORMATION
Corresponding Author
*E-mail: riccardo.salvio@uniroma1.it.
Notes
■
2 and 3 relative to 1 (Table 1) with Bronsted slope of 0.7 for this
̈
reaction (ref 5) leads to corrected krel values of 6.3 and 16.0 for 2 and
3, respectively.
The authors declare no competing financial interest.
(15) The small differences between the two sets of values arise from
the fact that the experiments on which k2 values are based were carried
out at pH values at which the mole fractions of the monoprotonated
forms of the catalysts are maximal but still slightly lower than unity in
all cases.
(16) Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. J. Chem. Soc., Trans.
1915, 107, 1080.
(17) Hammond, G. S. In Steric Effects in Organic Chemistry; Newman,
M. S., Ed.; John Wiley & Sons: New York, 1956.
ACKNOWLEDGMENTS
■
PRIN/MIUR 2008 and ATENEO La Sapienza 2010 are
acknowledged for financial support.
REFERENCES
■
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