Tetrahedron Letters 60 (2019) 1999–2004

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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet

Mechanistic study on the Knorr pyrazole synthesis-thioester generation

reaction
Yijun Du b, Yanyan Xu a, Chenze Qi a, Chen Wang a,⇑
a
Zhejiang Key Laboratory of Alternative Technologies for Fine Chemicals Process, Shaoxing University, Shaoxing 312000, People’s Republic of China
b
Yuanpei College, Shaoxing University, Shaoxing 312000, People’s Republic of China

a r t i c l e i n f o a b s t r a c t

Article history: A novel Fmoc-SPPS compatible peptide thioester generation method leveraging Knorr pyrazole synthesis
Received 29 April 2019 was reported recently. C-terminal peptide hydrazides, pentane-2,4-dione and excess arylthiol were
Revised 18 June 2019 added in one-pot to efficiently produce peptide thioesters in acidic aqueous solution at room tempera-
Accepted 25 June 2019
ture. To elucidate the detailed mechanism of this reaction and the origin of the effect of solution acidity,
Available online 25 June 2019
a theoretical investigation on the Knorr pyrazole synthesis-thioester generation reaction was carried out.
Our computational results suggest that the reaction generally proceeds through three stages: hydrazone
Keywords:
formation, pyrazole formation and thioester formation. The rate-determining step is the CAO bond cleav-
Knorr pyrazole synthesis
Thioester
age step in the pyrazole formation stage. The formed pyrazole is readily converted to thioester in the
Native chemical ligation presence of excess thiophenol. The effect of solution acidity originates from the need for protonation
Mechanism of oxygen atoms to increase the electrophilicity of carbonyl group or the leaving ability of hydroxyl group.
Theoretical calculations Ó 2019 Elsevier Ltd. All rights reserved.

Introduction

Chemical protein synthesis to introduce non-natural amino

acids into proteins and achieve special functions of proteins (such
as post-translational modification and probe-labeling) has been an
important complement to biological protein expression [1]. Lim-
ited by the size of peptides synthesized by solid-phase peptide syn-
thesis (up to about 50 amino acids), development of chemical
protein synthesis methods to conjugate peptide fragments has
been intensively studied for chemical protein synthesis [2]. Native
chemical ligation (NCL), developed by Kent et al. in 1994 [3], is one
of the most successful, effective and wildly-used methods for
chemical protein synthesis [4]. NCL utilizes two unprotected pep-
tides in which one with a C-terminal thioester and another with
an N-terminal cysteine, to react chemoselectively in aqueous solu-
tion under mild conditions, generating a peptide with the Cys liga-
tion site (Scheme 1a) [5]. Due to the intrinsic low stability of
thioesters to Fmoc solid-phase peptide synthesis (SPPS), efficient
and convenient synthesis of peptide thioesters [6] (or other acyl
donors as thioester surrogates [7]) has become a key issue in NCL
reactions. Recently, Dawson and co-workers have developed an
Fmoc-SPPS peptide thioester generation method leveraging Knorr
pyrazole synthesis [8] (Scheme 1b) [9]. In this method, C-terminal
⇑ Corresponding author.
E-mail address: wangchen@usx.edu.cn (C. Wang).
Scheme 1. (a) Native chemical ligation (b) Knorr pyrazole synthesis-thioester
generation reaction.
peptide hydrazides [10], pentane-2,4-dione and excess arylthiol
were added in one-pot to produce peptide thioesters in acidic
aqueous at room temperature. After adjusting the pH to 7, the
formed thioesters can undergo NCL directly with another N-termi-
nal cysteine. This method is fast, mild, easy to handle, and can be
used in multiple sequential ligations, providing a practical
approach for the generation of peptide thioesters. Interestingly,
Dawson et al. found that the pH of the solution has crucial influ-
ence on the reaction efficiency. When pH
4 the reactants can
be converted to the thioester in high yields whereas when
pH  7 no acyl pyrazole (as well as the thioester) was observed.
The Knorr pyrazole synthesis-thioester generation reaction
aroused our interest to investigate its mechanism and explore
the origin of the effect of solution acidity. In the previous study,

https://doi.org/10.1016/j.tetlet.2019.06.053
0040-4039/Ó 2019 Elsevier Ltd. All rights reserved.
2000 Y. Du et al. / Tetrahedron Letters 60 (2019) 1999–2004
although many literatures have proposed the mechanism of Knorr
pyrazole synthesis [11], there was a lack of systematic studies
(especially through theoretical calculations) for clarifying the
details. Only a few theoretical studies on the mechanism of forma-
tion of oxime have been done [12]. Here we report our theoretical
investigation of the mechanism of Knorr pyrazole synthesis-thioe-
ster generation reaction. The detail mechanism of the three stages
of the reaction, i.e. hydrazone formation, pyrazole formation and
thioester formation, were studied. It is found that the rate-deter-
mining step is the CAO bond cleavage (dehydration) in the pyra-
zole formation stage. The pyrazole can be readily converted to
thioester in the presence of excess thiophenol. The acidic condition
promotes this reaction by protonating carbonyl and hydroxyl
groups to increase their electrophilicity and leaving ability,
respectively.
Computational details
All the calculations were carried out using Gaussian 09 pack-
ages [13]. The geometry optimizations and frequency calculations
were performed using the M06-2X functional [14] with the Def2-
SVP basis set. Intrinsic reaction coordinate (IRC) [15] analysis of
each transition state was performed to confirm that it connects
the right reactant and product. Single-point energy calculations
were further performed on the optimized geometries using the
M06-2X functional with a larger basis set, i.e. Def2-TZVP. The
geometry optimizations, frequency calculations, and single-point
calculations were all simulated in aqueous solution with the
SMD model [16], corresponding to the reference state of 1 mol/L,
298.15 K (except water). Because the reaction occurs in aqueous
solution, the standard state of water corresponds to 55.5 mol/L,
298.15 K. The 3D structures were drawn using CYLview software
[17].
In this reaction, some steps involve the protonation of special
atoms of some structures. To estimate the energy change of these
processes, we first calculated the pKa of the protonated forms of
these structures, and then used Eq. (1) to obtain the Gibbs free
energy difference from these structures to their protonated forms
(see Supplementary Material for the method of calculating pKa
and the derivation of Eq. (1)).
DG ¼ 2:303RT ðpH  pK a Þ
where R is the gas constant, T is the absolute temperature and pH
refers to the degree of acidity of the solution.
Results and discussion
Model reaction
In Dawson’s experiment, peptide Ac-LYRAG-NH-NH2 (1 mM),
pentane-2,4-dione (2.5 eq) and thiophenol (2% v/v) were used to
synthesize thioester in a solution of 6 M GdmCl [9]. In considera-
tion of the calculation cost, a smaller peptide acylhydrazine model,
i.e. Ac-RAG-NH-NH2 was used in our computational mechanistic
study. The model reaction was shown in Scheme 2. As mentioned
above, the optimum reaction pH is 3, so we would investigate the
Scheme 2. Model reaction.
reaction mechanism at pH 3, and discuss the effect of pH on the
reaction efficiency in a separate section.
The reaction mainly proceeds through three stages: hydrazone
formation, pyrazole formation and thioester formation (Scheme 3).
These three stages will be discussed in turn below.
Hydrazone formation
The computed pathways for hydrazone formation are shown in
Fig. 1 and the optimized geometries of the transition states are
shown in Fig. 2. The hydrazone formation should initiate from
the nucleophilic attack of the amino N atom of R1 at the carbonyl
C atom of R2. Efforts to locate the transition state corresponding to
the direct attack were failed. Instead a water-assisted transition
state (TS1) for the nucleophilic attack was located, probably
because the water molecule stabilizes the transition state as well
as the formed zwitterionic intermediate INT2 by hydrogen bond-
ing. From INT2, proton transfer occurs via a water-assisted six
membered-ring transition state (TS3) to generate a hemiaminal
intermediate (INT4) [18]. INT4 can then simultaneously undergo
CAO bond cleavage and proton transfer via another water-assisted
six membered-ring transition state TS5, to form the hydrazone
intermediate INT6. The barriers of TS1, TS3 and TS5 are 21.4,
23.0 and 38.0 kcal/mol, respectively. Since the reaction occurs
under acidic conditions (pH = 3), we also considered the process
involving the protonated R2. The barrier for the nucleophilic attack
of R1 at the protonated R2 (assisted by a water molecule) is
16.6 kcal/mol (R1 + protonated R2 + H2O ? TS7), lower than that
for the nucleophilic attack of R1 at R2 (21.4 kcal/mol, R1 + R2
+ H2O ? TS1). This is because the protonation of the carbonyl oxy-
gen atom in R2 increases the electrophilicity of the carbonyl car-
bon atom. However, it should be noted that since the protonated
R2 is rather acidic (using acetone as the reference compound
(the pKa of its conjugate acid is 7), the pKa of the conjugate acid
ð1Þ
Scheme 3. General reaction process of the Knorr pyrazole synthesis-thioester
generation reaction.
Fig. 1. Computed pathways for hydrazone formation.
 Y. Du et al. / Tetrahedron Letters 60 (2019) 1999–2004 2001

Fig. 3. Computed pathways for pyrazole formation.

Fig. 2. Optimized geometries of the transition states for hydrazone formation (H

atoms bound to C atoms are hidden for clarity). Bond distances are in angstrom.

of R2 is calculated to be 3.9), the concentration of the protonated

R2 is very low in the solution.
Conversion of R2 to the protonated R2 corresponds to an energy
increase of 9.5 kcal/mol at pH 3 according to Eq. (1). Therefore, the
barrier of TS7 is actually 26.1 kcal/mol (R1 + R2 + H2O ? TS7). The
formed ammonium intermediate INT8 then converts to the oxo-
nium intermediate INT9 by acid-base equilibrium involving INT4.
INT9 subsequently undergoes CAO cleavage (via TS10) and depro-
tonation to generate the hydrazone intermediate INT6. The barrier
of TS10 is 16.3 kcal/mol. Taken together, for the hydrazine forma-
tion, the CAN bond formation and hemiaminal intermediate for-
mation should occur in neutral form and the CAO bond cleavage
should occur in cationic form. The most favorable mechanism for
the hydrazone formation proceeds through the process R1 + R2
+ H2O ? TS1 ? INT2 ? TS3 ? INT4 ? INT9 ? TS10 ? INT11 ?
INT6, and has a barrier of 23.0 kcal/mol (R1 + R2 + H2O ? TS3).
Fig. 4. Optimized geometries of the transition states for pyrazole formation (H
atoms bound to C atoms are hidden for clarity). Bond distances are in angstrom.
Pyrazole formation

Next, we turned our attention to the formation of the acyl-pyra-
zole, which is a key process for the preparation of thioester. The
computed pathways for pyrazole formation are shown in Fig. 3
and the optimized geometries of the transition states are shown
in Fig. 4. Generally, this process occurs through three steps: CAN
bond formation, CAO bond cleavage and deprotonation-aromatiza-
tion. Similar with the hydrazone formation, two possible pathways
(i.e. neutral pathway: Fig. 3 blue line and cationic pathway: Fig. 3
red line) for the pyrazole formation are proposed. For the neutral
pathway, the CAN bond formation accompanied by proton transfer
occurs via a water-assisted six-membered ring transition state
(TS12), generating a hemiaminal intermediate (INT13). From
INT13, the CAO bond cleavage and deprotonation-aromatization
occur simultaneously, also with the assistance of a water molecule
via a six-membered ring transition state (TS14), generating the N-
acyl pyrazole intermediate INT15. However, both TS12 and TS14
have very high barriers (INT6 ? TS12: 32.8 kcal/mol; INT13 ?
TS14: 45.7 kcal/mol), thus unlikely to be achieved. For the cationic
pathway, the c- carbonyl O atom of the acylhydrazone is proto-
nated first (INT16). Then the amide N atom attacks the keto C atom
via TS17, accompanied by proton transfer from the c- carbonyl O
atom to the keto O atom, to form a five-membered ring intermedi-
ate (INT18). INT18 can convert to an oxonium intermediate INT19
by acid-base equilibrium involving INT13. INT19 subsequently
undergoes CAO bond cleavage via TS20 to form INT21. Finally, a
water molecule removes a proton from the carbon atom of INT21
via TS22 to achieve the aromatization, delivering INT15. The CAN
bond formation via TS17 has a barrier of 18.5 kcal/mol (INT6 ?
TS17). The CAO bond cleavage via TS20 requires a barrier of
23.5 kcal/mol (INT13 ? TS20) and the water-induced deprotona-
tion-aromatization via TS22 requires a barrier of 19.6 kcal/mol
(INT13 ? TS22). According to the above results, the most favorable
2002 Y. Du et al. / Tetrahedron Letters 60 (2019) 1999–2004
mechanism for the formation of the pyrazole intermediate (INT15)
from the hydrazine intermediate (INT6) proceeds through the pro-
cess INT6 ? INT16 ? TS17 ? INT18 ? INT13 ? INT19 ? TS20 ?
INT21 ? TS22 ? INT15.
Thioester formation
Fig. 5 shows the most favorable pathway for the thioester for-
mation from the pyrazole intermediate (INT15) and thiophenol.
The optimized geometries of the transition states are shown in
Fig. 6. The nucleophilic addition of the N2-protonated acylpyrazole
(INT23) with thiophenolate anion requires a barrier of 13.2 kcal/-
mol (INT15 + PhSH ? TS24), forming a zwitterion intermediate
(INT25). Subsequent CAN bond cleavage of INT25 via TS26 has a
barrier of 9.1 kcal/mol (INT15 + PhSH ? TS26), generating the tar-
get product thioester (P1) and 3,5-dimethylpyrazole (P2). The low
barrier of the thioester formation (13.2 kcal/mol) suggests that it is
a kinetically facile process whereas the positive formation energy
(INT15 + PhSH ? P1 + P2, 3.2 kcal/mol) indicates that it is thermo-
dynamically unfavorable. In fact, in Dawson’s experiments, excess
thiophenol was added to the reaction system to shift the equilib-
rium to the right, towards the formation of thioester.
Overall mechanism
The overall mechanism of the Knorr pyrazole synthesis-thioe-
ster generation reaction is shown in Fig. S1 and the simplified
energy profile only including key intermediates and transition
states is shown in Fig. 7. It can be seen that among the three stages
the thioester formation has a significant low energy barrier
(13.2 kcal/mol, INT15 ? TS24). Thus, once the acyl-pyrazole inter-
mediate is formed, it can react with the thiophenol to generate the
Fig. 5. Computed pathways for thioester formation.
Fig. 6. Optimized geometries of the transition states for thioester formation (H
atoms bound to C atoms are hidden for clarity). Bond distances are in angstrom.
Fig. 7. Simplified Gibbs free energy profile of the overall mechanism.
final product thioester (note that excess thiophenol is required to
shift the equilibrium to the right). The hydrazine formation and
the pyrazole formation stages have similar barriers (23.0 kcal/mol,
R1 + R2 ? TS3 v.s. 23.5 kcal/mol, INT13 ? TS20). The overall bar-
rier of the reaction is 23.5 kcal/mol, corresponding to the CAO
bond cleavage step in the pyrazole formation stage, i.e. the rate-
determining step.
Origin of the effect of solution acidity
As mentioned above, the reaction was found to be greatly influ-
enced by the acidity of the solution. When pH
4 the reactants can
be converted to the thioester in high yields whereas at pH 7 no
pyrazole was observed but only moderate hydrazone was trapped.
Furthermore, at pH 8.5, only minute amounts of hydrazone is
observed, without any pyrazole and thioester. These results sug-
gest that both the hydrazone formation and pyrazole formation
are sensitive to the solution acidity while the latter is more sensi-
tive. From Fig. S1, it can be seen that in several steps, in order to
increase the electrophilicity of the carbonyl group or the leaving
ability of the hydroxy group, the O atoms are protonated, and the
energy of these O-protonated cationic species are related to the
pH of the solution (Eq. (1)). Table 1 presents the barriers of selected
key steps of the reaction at different pH. The proton transfer after
the CAN bond formation doesn’t change with the pH because TS3
is neutral (Table 1, entry 1). In contrast, the barrier of the CAO
bond cleavage (INT4 ? TS10) increases as the pH increases
(Table 1, entry 2), and there is actually a linear correlation between
them (Eq. S3). This is because the CAO bond cleavage requires the
hemiaminal intermediate INT4 to be protonated. When the pH
increases, the protonation efficiency (or the concentration of dehy-
dration precursor) decreases, so the corresponding energy barrier
increases. Similarly, the barriers of the CAN bond formation and
CAO bond cleavage steps in the pyrazole formation both signifi-
cantly increase as the pH increases (Table 1, entries 3 and 4, Eq.
S4 and Eq. S5). To be specific, at pH 3 the barrier of the hydrazone
formation stage is 23.0 kcal/mol and the barrier of the pyrazole for-
mation is 23.5 kcal/mol. So the reaction has an overall barrier of
23.5 kcal/mol and can happen at room temperature. At pH 7, the
barrier of the hydrazone formation stage is still 23.0 kcal/mol
Table 1
Gibbs free energy barriers of selected key steps of the reaction at different pHs.
Entry Barrier (kcal/mol) pH = 3 pH = 7 pH = 8.5
1 R1 + R2 ? TS3 23.0 23.0 23.0
2 INT4 ? TS10 16.3 21.7 23.8
3 INT6 ? TS17 18.4 23.9 25.9
4 INT13 ? TS20 23.5 29.0 31.0
 Y. Du et al. / Tetrahedron Letters 60 (2019) 1999–2004
whereas that of the pyrazole formation increases to 29.0 kcal/mol
which is too high for being overwhelmed at room temperature.
Because the formation of the hydrazone is exoenergetic (-1.4 kcal/-
mol, R1 + R2 ? INT6), the reaction stops after formation of the
hydrazone. At pH 8.5, the barrier of the hydrazone formation stage
increases to 23.8 kcal/mol, corresponding to the CAO bond cleav-
age step in the hydrazone formation stage. Therefore, the efficiency
for the formation of the hydrazone declines, leading to reduced
hydrazone as observed in the experiments.
Conclusion
[5]
Systematic study on the mechanism of Knorr pyrazole synthe-
sis-thioester generation reaction was carried out with the aid of
DFT calculations. It is found that the previously-proposed mecha-
nism including three stages of hydrazone formation, pyrazole for-
mation and thioester formation is reasonable with a calculated
energy barrier of 23.5 kcal/mol under the condition of pH = 3.
The thioester formation is kinetically favored but thermodynami-
cally unfavored. In the presence of excess thiophenol, once the
pyrazole is formed, it is readily converted to the target thioester.
The rate-determining step of the reaction is the CAO bond cleavage
step in the pyrazole formation stage. The hydrazone formation and
[6]
pyrazole formation stages are greatly affected by the acidity of the [7]
solution while the latter is more sensitive. The efficiency of the
reaction depends on the pH because some steps in the reaction
require the protonation of oxygen atoms to increase the elec-
trophilicity of carbonyl group or the leaving ability of hydroxyl
group, making acidic condition suitable for this reaction.
Acknowledgment
This research was supported by Zhejiang Provincial Natural [8]
Science Foundation of China under Grant No. LY18B020007. All cal- [9]
culations in this study were performed on the supercomputer Cen-
[10]
ter of Shenzhen.
Appendix A. Supplementary data
Method of calculating pKa, the derivation of Eq. (1), Linear cor-
relation between the cationic transition states (TS10, TS17 and
TS20) and pH, overall mechanism of the Knorr pyrazole synthe-
sis-thioester generation reaction, thermal correction to Gibbs Free
[11]
Energies, single-point electronic energies and Cartesian coordi-
nates of reactants, intermediates and transition states. This mate-
rial associated with this article can be found online at https://doi.
org/10.1016/j.tetlet.2019.06.053.
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