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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5262_Библиотеки_им_академика_М_И_Перельмана.pdf
1 Opinions and Suggestions8
1.10 Always Learn Something from the Reaction
You Performed
Every reaction we conduct, whether it succeeds or fails, offers valuable lessons.
Understanding why a reaction worked is essential for successful reactions.
Conversely, for unsuccessful ones, we need to analyze why they failed. Was there no
reaction at all, or was an unexpected product formed? What caused the outcome?
Identifying the root cause of a problem makes it easier to find a solution. Failure
itself isn’t the issue; the real problem lies in not understanding why it happened or
failing to uncover the true reason behind the failure.
1.11 Knowing Reaction Mechanisms Alone Doesn’t
Make an Excellent Chemist—But It’s Essential
Understanding the mechanisms of organic reactions is essential for becoming
an outstanding synthetic medicinal chemist, but it is not enough on its own.
To excel in any profession, you must first have a genuine passion for it. As a
synthetic chemist, you also need to possess exceptional practical skills, a strong
work ethic, and unwavering perseverance. Success belongs to those who remain
steadfast in their beliefs. These qualities are the cornerstone of the scientific
spirit. Understanding reaction mechanisms is like having a clear path before you,
making it easier to reach your goals. Conversely, not understanding these mech-
anisms is like running in the dark—you are more likely to stumble or fall into
obstacles along the way.
1.12 Patents Do Not Tell You the Full Story
of Chemistry
As a medicinal chemist regularly engaged in synthetic work, you will frequently
consult reactions documented in patents. However, it’s important to recognize the
significant differences between patents and journal articles. Patents typically do not
include detailed reaction mechanisms. If new methods are disclosed, they often
only present the results without explaining the rationale or development process
behind the innovation. Additionally, patents rarely cite references for the synthetic
methods they employ. The yields reported in patents are usually not optimized and
may even be inaccurate, meaning they should only be used as a rough guideline
rather than a reliable benchmark for calculating the yield of your own synthetic
routes. In some cases, yields may not be provided at all. Furthermore, the character-
ization data for intermediates and final products in patents is often incomplete or
insufficiently detailed.
1.14 Two Examples 9
1.13 Summarize Your Work After Completing
a Synthesis
Once a synthesis is completed, it is important to promptly create a summary.
Throughout the synthesis process, you may have faced challenges, encountered
difficulties, or taken unnecessary detours. Now that you have gained insights into
resolving these issues and avoiding similar pitfalls in the future, it is an opportune
time to reflect on whether there are more efficient synthesis methods or improved
approaches. Writing a summary not only enhances your writing skills but also sig-
nificantly strengthens your ability to summarize, as well as your logical and analyt-
ical thinking.
1.14 Two Examples
Here I would like to present two examples to illustrate the importance of under-
standing reaction mechanisms in solving chemistry problems.
One example is selected from our research experience and the results were pre-
sented in a patent application [1]. In a medicinal chemistry project, we wanted to
synthesize a series of platelet-derived growth factor receptor inhibitors, which struc-
ture is shown in the scheme below as compounds 11. Those compounds consist of the
core structure, named as a 2,7-naphthyridin-3(2H)-one. Our synthetic plan included
the reductive amination of the key intermediate 16, then cyclization, de-protection of
2,4-dimethoxybenzyl (DMB) and oxidation to form the amino pyridine 12.
It seems in the above design, each step is reasonable. However, when the reduc-
tive amination of 16 with DMBNH
2
with NaBH(OAc)
3
in 1,2-dichloroethane was
performed, the expected product 15 was not obtained. Instead, a cyclized product
17 was obtained in 37% yield. That was the key intermediate for the synthesis of
our target compounds. Understanding the mechanism for the formation of 17 from
16 was crucial for us for developing a practical synthesis of 11. The formation of 17
could be explained by the following mechanism. Since the commercially available
NaBH(OAc)
3
always contains residual HOAc, which can be easily smelled when you
open the chemical container, trace amount of HOAc catalyzed the formation of 17.
O
N
N
NH
Ar
R
Ar
N
16
O
CN
O
DMBNH
2
reductive
amination
Ar
N
O
CN
NHDMB
11
15
Cyclization
Ar
N
O
N
14
DMB
Ar
N
O
NH
13
Oxidation
Ar
N
O
N
12
NH
2
NH
2
Reductive
amination
Deprotection
NH
2
1 Opinions and Suggestions10
Based on this mechanism, NaBH(OAc)
3
should not play any role for the formation
of 2,7-naphthyridin-3(2H)-one (17) and the reaction should be catalyzed by acid.
Thus, a preparation of 17 from 16 and DMBNH
2
catalyzed by HOAc was designed
and performed. To our delight, the reaction gave the desired product in quantitative
yield.
Encouraged by the above discovery, when methylamine was employed as a sub-
strate, the desired product 11a was produced in a single step in quantitative yield.
As methylamine was used as an aqueous solution, a phase transfer catalyst, Bu
4
NBr
(0.25 eq), was also added.
Thus, an excellent procedure for synthesis of 2,7-naphthyridin-3(2H)-ones was
developed by understanding the mechanism of the formation of an unexpected
product [1].
The second example is selected from the work of Bristol-Myers Squibb Company.
Pexacerfont (18) is a pyrazolotriazine corticotropin-releasing factor receptor 1
(CRF1) antagonist. During a process study, chemists investigated the chlorination of
19 by POCl
3
catalyzed by tertiary amines [2]. In the presence of DABCO (1 mol %),
the desired chloropyrazolotriazine 20 was obtained in 78% yield within 1 h at 20 °C.
Ar
N
16
O
17
O
NH
2
DMB
Ar
N
O
O
NH
NHDMB
Ar
N
O
O
NHDMB
Ar
N
O
OH
N
NHDMB
Ar
N
O
N
NHDMB
N
H
+
H
H
+
NH
2
−H
2
O
16
O
CN
O
DMBNH
2
(1.6 eq.)
DCE, HOAc (1 eq.)
rt, 20 h
99%
Ar
N
17
O
N
NHDMB
Ar
N
Ar
N
16
O
CN
O
MeNH
2
(aq, 10 eq.)
DCE, HOAc (12 eq.)
Bu
4
NBr(0.25 eq.)
70 °C, seal tube, 20 h
99%
Ar
N
11 a
O
N
N
H
1.14 Two Examples 11
While an impurity 21 (<0.5%) was also generated. Since this impurity is a potential
alkylating agent and would interfere with the next reaction, its level required close
monitoring in the final product. How this impurity was produced and how to avoid
its formation?
The formation of 21 was the result of nucleophilic attack of DABCO on the pro-
posed O-phosphorylated intermediate 22. Presumably, chloride ion displacement of
DABCO (path a) provides the desired product 20. Conversely, attack at either of the
three ɑ-carbons of the activated DABCO intermediate 23 (path b) would produce
impurity 21.
Realizing that side-reaction, the chemists from BMS used 0.5 mol % of
N-methylmorpholine (NMM), leading to >98% conversion to 20 within 1 h at 25 °C,
although a trace amount of the amination impurity 24 still formed in analogy to
the DABCO catalyzed reaction. Importantly, the chlorinated impurity B, analo-
gous to 21, was not observed. Since the chloride ion would presumably attack the
primary methyl group of NMM, only trace amounts of chloromethane—a volatile
impurity—would form and likely evaporate during the reaction and workup. Thus,
no alkylating impurity existed in the products.
OMe
NN
N
N
NH
Pexacerfont (18)
OMe
NN
N
N
OH
19
N
N
OMe
NN
N
N
Cl
20 (78%)
OMe
NN
N
N
N
21 (<0.5%)
N
Cl
+
NH
2
DABCO
POCl
3
, AcCN
DABCO (1%)
20 °C, 1h
OMe
NN
N
N
O
19
Cl
P
Cl
O
Cl
H
HCl
OMe
NN
N
N
O
P
Cl
O
Cl
N
N
N
N
OMe
N
N
N
N
N
N
+
a
b
N
N
path b
20
OMe
NN
N
N
N
N
Cl
PO
2
Cl
+
Cl−
22
23
21
CI
–
path a
1 Opinions and Suggestions12
References
1 Zhang, W.; Wang, X.; Liu, H.; Zhou, Z.; Wang, Y.; Yang, L.; Li, T.; Zhao, X.; Zou, Z.;
Gao, Y.; Lin, S.; Wang, W. WO 2020/063860 A1.
2 Broxer, S.; Fitzgerald, M. A.; Sfouggatakis, C.; Defreese, J. L.; Barlow, E.; Powers,
G. L.; Peddicord, M.; Su, B.-N.; Tai-Yuen, Y.; Pathirana, C.; Sherbine, J. P. Org.
Process Res. Dev., 2011, 15, 343.
OMe
NN
N
N
O
19
Cl
P
Cl
O
Cl
H
HCl
OMe
NN
N
N
O
P
Cl
O
Cl
O
N
N
OMe
NN
N
N
Cl
–
a
b
O
N
path b
path a
20
OMe
NN
N
N
N
O
24
PO2Cl
+
Cl–
22
A
MeCl
NMM
OMe
NN
N
N
N
O
B (not detected)
Cl
O
O
N
+
This chapter collects some terms and concepts mainly related to organic reaction
mechanisms, process chemistry, and medicinal chemistry and introduces these
terms and concepts as concise as possible. Almost every term or concept could be
written in a book. This is indeed the case. Obviously, these introductions are not
an encyclopedia of terms and concepts in synthetic organic chemistry. With the
discussion of “stereoselectivity” in this chapter, I deliberately avoided stereo-
chemistry and asymmetric synthesis, two important topics in organic chemistry
due to two reasons. First, because these topics are too vast to explain clearly in a few
short paragraphs; second, they have been discussed in detail in the literature.
2.1 Reaction Mechanism
In chemical reactions, a mechanism is a story that tells the detailed process of
compound A being transformed into compound B under given reaction conditions.
The reactions themselves may involve the interaction of atoms, molecules, ions,
electrons, and free radicals. Organic reaction mechanisms form the foundation for
understanding organic chemistry.
2.2 Approaches to Draw Reaction Mechanism
There may be more than one reasonable mechanism that can be drawn for a reac-
tion. In general, a mechanism explains the detailed process from starting materials
to products, which may involve some intermediates, transition states, ions, and/or
free radicals. Transformations can be indicated by straight arrows between those
species in a linear manner. A curve arrow represents transfer of one pair of elec-
trons. Hook or fish hook represents single electron transfer in free radical reactions.
For noncatalytic reactions, the mechanism is usually drawn in a linear way. While
for catalytic reactions, the mechanism can be drawn in two different ways, linear and
cyclic. For example, the general catalytic cycle for Suzuki cross coupling involves three
fundamental steps: oxidative addition, transmetalation, and reductive elimination as
2
General Terms and Concepts in Synthetic Organic
Chemistry
2 General Terms and Concepts in Synthetic Organic Chemistry14
demonstrated in the following scheme. Oxidative addition of aryl halides to Pd(0)
complex is the initial step to give intermediate I, a Pd(II) species. With the participa-
tion of base, an organoboron compound reacts with intermediate I in transmetalation
to afford intermediate II. This is followed by reductive elimination to give the desired
product and regenerate the original Pd(0)-Ln, the catalyst species [1].
2.2.1 Linear Way: Catalytic and Noncatalytic Reactions
2.2.2 Cyclic Way: Catalytic Reactions
2.3 Desired Product
Desired product, also called the expected product, is the product expected or
predicted to be obtained from a reaction.
2.4 Unexpected Product
Unexpected product is the product that is not expected to be a product from a
reaction. Due to the complexity and the reactivity of starting materials and prod-
ucts, under the reaction conditions, unexpected or undesired products are often
obtained. The formation of unexpected products is also reasonable. Interpreting the
formation mechanism can sometimes lead to the discovery of a new reaction or a
new synthetic method.
+
Pd(0)-Ln
Oxidative
addition
Pd(II)-Ln
X
I
Transmetalation
Base
Pd(II)-Ln
II
X
B(OH)
2
Reductive
elimination
Pd(0)-Ln
product
catalyst
Back to
catalytic cycle
Ar
1
Ar
2
B(OH)
2
Ar
2
Ar
1
XAr
1
Ar
1
Ar
2
Base
Pd(0)-Ln
Oxidative
addition
Pd(II)-Ln
X
I
Pd(II)-Ln
II
Transmetalation
Reductive
elimination
product
Ar
1
Ar
2
Ar
1
Ar
2
B(OH)
2
X
B(OH)
2
XAr
1
Ar
2
Ar
1
2.7 Impurity 15
2.5 Side Reaction
A side reaction occurs simultaneously with the main reaction, to a lesser extent
and results in the formation of side products, thereby reducing the yield of the
main product. Imagine transporting oil through a pipeline: if there are leaks along
the way, the amount of oil received at the destination will be less than what was ini-
tially supplied. Similarly, a side reaction, often called a competing reaction, affects
the overall efficiency of the process. This concept is closely tied to reaction selec-
tivity. If a reaction has 100% selectivity, no side products are formed, analogous to a
pipeline with no leaks.
2.6 Side Product and By-product
Due to chemo-, regio-, or stereoselectivity issues, side reactions take place in many
organic reactions. A side product is produced from a side reaction.
Different from a side product, a by-product is an inevitable component produced
from the main reaction and accompanies the desired product. It is a non-negligible
component of the reaction. Therefore, a by-product may also be called an accom-
panying product. There is no such a term as “by-reaction” in chemistry since the
by-product is generated from the main reaction.
A side product can be suppressed, reduced, or eliminated under optimal reac-
tion conditions. However, a by-product cannot be avoided unless the chemistry
being carried out or the reagent(s) used are changed.
For example, when a mono-alkylation of aniline with phenethyl tosyl-
ate was performed, N-phenethylaniline was the desired product (yield 86%),
N,N-diphenethylaniline was the side product (yield 6%), and p-toluenesulfonic
acid was the by-product [2]. The yield of the side product, N,N-diphenethylaniline,
can be reduced by increasing the equivalents of aniline; however, formation of the
by-product, p-toluenesulfonic acid, cannot be avoided.
2.7 Impurity
Impurities are undesired compounds present in a desired compound. They may
come from by-products, side products, starting materials, reagents, catalysts, or
solvents.
Ph
NH
2
+
TsO
Ph
Phenethyl tosylate
(1 eq.)
KI (0.1 eq.)
CH
3
CN
Ph
H
N
+
Ph
N
Ph
Ph
Ph
+
Aniline (3 eq.)
TsOH
N-phenethylaniline
desired product
yield 86%
N,N-diphenethylaniline
side product
yield 6%
p-toluenesulfonic
acid
by-product
170 °C, 10 min
microwave
2 General Terms and Concepts in Synthetic Organic Chemistry16
2.8 Theoretical Yield, Percentage Yield (Yield),
Net Yield, and Overall Yield
In a chemical reaction, reactants that are not completely used up are called
excess reagents, and reactants that are completely consumed are called limiting
reagents. The amount of a product formed from the complete reaction of a limiting
reagent is called the theoretical yield, whereas the actual amount of a product
produced is the actual yield. The ratio between the actual yield and the theoret-
ical yield expressed in percentage is called the percentage yield, also commonly
known as yield. Chemical reaction equations give the ideal stoichiometric relation-
ship between reactants and products. Thus, the theoretical yield can be calculated
from the reaction stoichiometry. For many chemical reactions, the actual yield is
generally less than the theoretical yield, apparently due to the loss in the process,
side reactions, or inefficiency of the chemical reaction.
Sometimes, a reactant is not 100% converted into a product. The reaction
can be pushed toward the product by approaches such as prolonging the reac-
tion time or raising the reaction temperature. However, these approaches often
increase formation of side products. If the reactant is expensive and can be easily
recovered from the reaction mixture by separation and purification process, we
would rather sacrifice the conversion rate and reduce the reaction complexity.
The amount of a product based on the actual consumption of the reactant is
called the net yield.
For a multistep synthesis, the overall yield of the final product is calculated by
multiplying the yield of each step. This overall yield is crucial for planning a multi-
step synthesis. For example, for an eight-step synthesis, assuming the yield of each
step is 80%, then the overall yield is 80% × 80% × 80% × 80% × 80% × 80% × 80% ×
80% = 17%. If the molecular weight of the starting material is 100 daltons (Da) and
the final product is 400 daltons (Da), and if 1 g of the final product needs to be
synthesized, then at least 1.00 g × 100/400/0.17 = 1.49 g of the starting material is
needed. To account for retaining intermediates at each step and to prepare for unex-
pected potential issues, the first step is typically performed on a scale three times
larger—requiring about 5 g of the starting material.
The overall yield can also be used for expressing multistep one-pot reactions
and telescoped reactions, as these processes usually include more than one
reaction.
2.9 Intermediate
In the synthesis or production of a compound, all the substances generated in one
step and used for the succeeding step are considered intermediates. In descrip-
tions of organic reaction mechanisms, certain unstable molecules—such as free
radicals, carbenes, carbonium ions, and carbanions—are known or hypothesized
to be intermediates, even if they have not been isolated. These intermediates are
highly reactive fragments of molecules that generally remain uncombined for only
very short periods.
2.15 Material Balance 17
2.10 Transition State
The transition state in a chemical reaction represents a specific configuration along
the reaction pathway. It is characterized as the point of maximum potential energy on
the reaction coordinate. According to the transition state theory, once the reactants
reach this transition state and surpass it, they invariably proceed to form products.
2.11 Species
A chemical species is a chemical substance that can be an atom, molecule, ion, or
radical. Species are often used to represent intermediates in a reaction mechanism.
2.12 Free Radical
A free radical, often simply referred to as a radical, is an atom, molecule, or ion
that possesses at least one unpaired valence electron. In most cases, these unpaired
electrons render radicals highly reactive in chemical reactions. Many radicals tend
to spontaneously dimerize. Also, the majority of organic radicals exist only briefly
due to their short lifetimes.
2.13 Stoichiometric Reaction
A stoichiometric reaction is one in which the quantities of reactants and products
are balanced such that all of the reactants are consumed and none remain after
completion of the reaction. In other words, all reactants and reagents need to be
added in amounts at least matching the reaction equation.
2.14 Catalytic Reaction
Catalysis refers to speeding up a chemical reaction and lowering the temperature
required for it by introducing a substance called a catalyst. Catalysts are not used up
in the reaction, and they retain their original form throughout the reaction. In cases
where the reaction is fast and the catalyst is rapidly reused, even tiny quantities of
the catalyst may be sufficient. Typically, catalysts react with reactants and produce
intermediate substances. These intermediates break down to form final products of
the reaction, and the catalyst is restored to its initial state for continued use.
2.15 Material Balance
A material balance, often referred to as a mass balance, applies the law of mass
conservation to organic reactions. This principle dictates that mass cannot be spon-
taneously created or destroyed. In a reaction mechanism, some small molecule
by-products, such as H
2
O, CO, CO
2
, NH
3
, HCl, etc., should not be ignored.