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2 General Terms and Concepts in Synthetic Organic Chemistry18
2.16 Electron Balance
Electron balance, also known as charge balance, is the conservation of electrons
in an organic reaction. Since electrons are also a form of matter, in a reaction mech-
anism, the total number of electrons in the reactants must equal the total number
of electrons in the intermediates and the products. In a reaction mechanism, some
ions, salts, or radicals may be involved, but the total number of charges in the reac-
tants must equal the total number of charges in the intermediates and the products.
In a redox reaction, if one species is oxidized, another species must be reduced.
2.17 Nucleophile
A nucleophile is a chemical species that forms bonds by donating an electron pair.
All molecules and ions with a free pair of electrons or at least one π bond can act as
nucleophiles. Because nucleophiles donate electrons, they are Lewis bases. The term
nucleophilic describes the affinity of a nucleophile to bond with positively charged
atomic nuclei. Nucleophilicity, also called nucleophile strength, refers to a substance’s
nucleophilic character and is often used to compare the affinity of atoms. Nucleophiles
may take part in nucleophilic substitution and nucleophilic addition.
2.18 Electrophile
Any molecule, ion, or atom that is deficient in electrons in some way is called an
electrophile. Electrophiles can accept a pair of electrons. These are types of species
that tend to attract electrons (philic). The reactions between electron donors and
acceptors are described by concepts such as electrophile and nucleophile, which are
the most important concepts in organic chemistry.
2.19 Acid
An acid is a molecule or ion capable of either donating a proton, known as a
Brønsted–Lowry acid, or forming a covalent bond with an electron pair, known
as a Lewis acid. Hydrogen chloride, acetic acid, and most other Brønsted–Lowry
acids cannot form a covalent bond with an electron pair and are therefore not Lewis
acids. Conversely, many Lewis acids are not Arrhenius or Brønsted–Lowry acids. In
modern terminology, an acid is implicitly a Brønsted–Lowry acid and not a Lewis
acid, since we always refer to a Lewis acid explicitly as a Lewis acid.
2.20 Base
In chemistry, there are three definitions for the word “base”—Arrhenius bases,
Brønsted–Lowry bases, and Lewis bases, all of which agree that bases are
substances that react with acids.
2.22 Acid–Base Reaction 19
Arrhenius proposed that a base is a substance which dissociates in an aqueous
solution to form hydroxide ions OH
−
. According to the more general Brønsted–
Lowry acid–base theory, a base is a substance that can accept hydrogen cations (H
+
).
The Lewis theory states that a base is an electron pair donor that can share a pair of
electrons with an electron acceptor, which is a Lewis acid.
Basicity is closely related to nucleophilicity. The difference between the two is that
basicity is a thermodynamic property (i.e., relates to an equilibrium state), whereas
nucleophilicity is a kinetic property, which relates to rates of certain chemical
reactions).
2.21 Acidity and pK
a
In chemistry, an acid dissociation constant (also known as acidity constant or acid
ionization constant, denoted by K
a
) is a quantitative measure of the strength of an
acid in solution. It is the equilibrium constant for a chemical reaction
known as dissociation in the context of acid–base reactions. The chemical species
HA is an acid that dissociates into A
−
, the conjugate base of the acid and a hydrogen
ion, H
+
.
The dissociation constant is defined by
The higher the K
a
of an acid, the stronger the acidity. In other words, the higher
the pK
a
of an acid, the stronger the basicity of its conjugate base.
2.22 Acid–Base Reaction
An acid–base reaction is simply the transfer of a proton from an acid to a base.
When the acid gives up a proton, the species remaining still retains the electron
pair to which the proton was formerly attached. The new species can reacquire
a proton and is referred to as the conjugate base of the acid. All acids have a
conjugate base, and all bases have a conjugate acid. An acid–base reaction fits the
equation
HA
A
–
+
H
+
K
a
=
[A
–
][H
+
]
[A
–
][H
+
]
[HA]
pK
a
= –log
10
[HA]
K
a
= log
10
A
A
+
H
+
B
H B
Acid
1
Base
2
Base
1
Acid
2
2 General Terms and Concepts in Synthetic Organic Chemistry20
Base
1
is the conjugate base of Acid
1
, and Acid
2
is the conjugate acid of Base
2
.
To push the reaction to the right side of the equation, pK
a
of Acid
2
must be greater
than pK
a
of Acid
1
.
Whether a compound is an acid or a base depends on the role it plays in the reac-
tion. For example, aniline is a base in the following reaction:
In the following reaction, aniline is an acid:
2.23 Reaction Selectivity
Selectivity problems arise when more than one reaction is possible for a given reac-
tion. This is one of the fundamental aspects of chemical reactions, where reactions
tend to occur in specific ways, producing specific products. Selectivity in organic
chemistry plays a crucial role in determining the outcome of reactions and is critical
for the synthesis of complex molecules with desired properties. To achieve this goal,
it is important to understand selectivity in organic chemistry and its importance in
synthetic reactions to produce the desired product with the desired stereochemistry
and minimize side products.
2.24 Chemoselectivity
Chemoselectivity means a chemical reagent reacts more readily with one functional
group over another when multiple different functional groups are present. Another
class of chemoselectivity is to control a reaction at one functional group to a desired
stage, such as reducing an ester to aldehyde rather than primary alcohol.
For example, there are two carbonyl groups in 4-acetylbenzaldehyde (1):
the aldehyde group and the ketone group. When 1 was reduced with a catalyst
system consisting of Fe(BF
4
)
2
+ 6H
2
O and P(CH
2
CH
2
PPh
2
)
3
[tetraphos, (PP
3
)] in
THF, the aldehyde group was chemoselectively reduced to the primary alcohol
1-(4-(hydroxymethyl)phenyl)ethan-1-one (2) [3]. However, the ketone group was
preferentially reduced to 4-(1-hydroxylethyl)benzaldehyde (3) in 93% selectivity
with diborane on silica gel by first forming an adduct of the more reactive car-
bonyl group with sodium bisulfite [4].
NH
2
+
H Cl
Aniline
base
Hydrochloric
acid
Aniline hydrochloride
salt
N
+
H
3
CI
–
NH
2
+
N
–
HLi
+
Aniline
acid
n-Butyllithium
base
Lithium anilide
base
n-BuLi
+
n
-Butane
acid
n-BuH
2.26 Stereoselectivity 21
There are many categories under the term “chemoselectivity.” Examples include
the Dess–Martin oxidation [5] and the Swern oxidation [6], both of which selectively
convert primary alcohols to aldehydes without further oxidation to carboxylic acids.
2.25 Regioselectivity
Regioselectivity describes the propensity of a chemical reaction to favor bond
formation or cleavage at a specific site over other potential locations. This principle
often dictates where a reagent interacts within a molecule—such as the selective
removal of a particular proton by a strong base or the positioning of a new substit-
uent on an aromatic ring already bearing functional groups. It plays a critical role
in reactions where molecules contain multiple reactive sites, guiding the process to
occur predominantly at one location.
A classic illustration is the Baeyer–Villiger oxidation, in which an oxygen atom is
introduced adjacent to a carbonyl group. In ketones, this insertion is directed toward
the carbon atom with greater substituents, reflecting electronic or steric influences.
For instance, studies on acetophenones demonstrate that oxygen incorporation
is favored between the carbonyl group and the aromatic ring, resulting in phenyl
acetate formation rather than methyl benzoate [7]. This outcome underscores
how regioselectivity governs product distribution by prioritizing specific reaction
pathways.
2.26 Stereoselectivity
Stereoselectivity refers to the tendency of a chemical reaction to produce stereoiso-
mersinunequalproportionswhena newstereocenteris formednon-stereospecifically
or when an existing stereocenter undergoes non-stereospecific modification.
O
O
O
HO
O
O
OH
O
1
2
1
3
99%
93%
Fe(BH
4
)
2
.6H
2
O/PP
3
(0.4%)
HCO
2
H (1.1 eq.)
THF, 60 °C, 2 h
1. NaHSO
3
(2 eq.)
dioxane-H
2
O (1:2), rt, 1 h
2. Silica gel
3. Diborane
4. aq. NaOH
X
O
m-CPBA
CHCl
3
, 32 °C
X
O
O
2 General Terms and Concepts in Synthetic Organic Chemistry22
The ratio of stereoisomers generated can vary widely. While both products are the-
oretically possible, they typically form in distinct quantities. In some cases, depend-
ing on reaction conditions and analytical sensitivity, the minor stereoisomer may
not be observed using the detection methods available.
Stereoselectivity can be classified into three basic types. The first is that an
achiral or prochiral structural unit undergoes a reaction to form a chiral unit
and produces unequal amounts of stereoisomers. All asymmetric reactions are
stereoselective reactions. The asymmetric reduction of acetophenone to (R)- or
(S)-(-)-1-phenylethan-1-ol is a stereoselective reduction [8]. The possible two
products of this reaction are enantiomers. The stereoselectivity of an asymmetric
reaction can be determined by enantiomer excess (ee). Enantiomeric excess (ee)
is also a measurement of purity of chiral substances. It reflects the degree to which
a sample contains one enantiomer in greater amounts than the other. A racemic
mixture has an ee of 0%, while a single completely pure enantiomer has an ee
of 100%.
The Diels–Alder reaction is both regioselective and stereoselective, although it
typically produces a racemic mixture of two enantiomers. For example, in a ste-
reocontrolled total synthesis of (+/−)−tabersonine, the Diels–Alder cycloaddition
reaction between diene 1 and ethacrolein 2 proceeded with complete regiocontrol
and excellent endo selectivity to produce adduct 3 in 97% yield [9].
The second type of stereoselectivity is the reaction of symmetrical cyclic com-
pounds to produce unequal amounts of cis-trans isomers. A typical example is
the reduction of 4-(tert-butyl)cyclohexan-1-one to cis- and trans-4-(tert-butyl)
cyclohexan-1-ol. With the use of lithium methyl borohydride as a reducing agent,
the proportion of more stable trans product reached 98.3%, whereas with NaBH
4
,
the trans/cis ratio was only 86:14 [10].
O
OH
Acetophenone
(S)-1-phenylethan-1-ol
(99%)
OH
+
(R)-1-phenylethan-1-ol
(1%)
ee 98%
yield 72%
)
(−)-Ipc
2
BCI
THF, –25 °C
2
BCI
MeO
2
C
N
TBSO
1
+
OHC
2
Toluene
85 °C
97%
TBSO
N
CHO
3 (racemic)
Steps
N
H
N
(+/–)-tabersonine
MeO
2
C
CO
2
Me
2.27 Iteroselectivity 23
The third type of stereoselectivity is a reaction that produces a C═C or C═N dou-
ble bond and produces unequal amounts of Z/E-isomers, also called geometric
isomers. The dehydrohalogenation of 2-iodobutane demonstrates moderate stere-
oselectivity, producing trans-2-butene as the major product (60%) and cis-2-butene
as the minor product (20%) [11].
The Wittig reaction is generally stereoselective, with the geometry of the result-
ing alkene dependent on the type of ylide employed. The reaction of aldehydes
with unstabilized ylides (where R
2
= alkyl groups) favors the formation of the
(Z)-alkene with moderate-to-high selectivity. This preference can be amplified to
near-exclusive Z-selectivity when conducted in dimethylformamide (DMF) with
lithium iodide or sodium iodide as additives. Conversely, stabilized ylides (where
R
2
= electron-withdrawing groups such as esters or ketones) predominantly yield
the (E)-alkene with high selectivity [12].
2.27 Iteroselectivity
Iteroselectivity describes the selectivity when a given reaction can occur at
least twice on a substrate (e.g., alkylation of a symmetric diol and protection of a
symmetric diamine) but selectively stops after a given number of iterations. This
is a long-standing and challenging practical problem. Roy Lavendomme and Ivan
Jabin recently named this type of selectivity “iteroselectivity” and their work was
published in Cell Reports Physical Science [13].
O
OH
+
OH
Cis-4-(tert-butyl)cyclohexan
-1-ol
Trans-4-(tert-butyl)cyclohexan
-1-ol
Conditions
Conditions: A, LiBH
3
CH
3
, Et
2
O, –78 °C. cis : trans = 1.7 : 98.3
B, NaBH
4
, diglyme. cis : trans = 14 : 86
4-(tert-butyl)cyclohexan
-1-one
I
t-BuOK
DMSO
+
+
60% trans
20% cis 20% 1-butene
Stereoselectivity
Regioselectivity
O
+
+
Ph
3
P
Trans
or (E)-isomer
Cis
or (Z)-isomer
R
1
R
2
R
1
R
2
R
1
R
2
2 General Terms and Concepts in Synthetic Organic Chemistry24
This new selectivity concept is defined and compared with the classical chemo-,
regio-, and stereoselectivities encountered in chemical synthesis. Examples of
iteroselective reactions range from very common reactions such as electrophilic aro-
matic substitution to advanced methods involving large supramolecular complexes.
Unlike traditional isomers, iteromers are not considered isomers because they
have different molecular formulas.
The comparison between regioselectivity and iteroselectivity is shown in the
following example of bromination of anisole.
Bromination of anisole with photodecomposed brominated methanes could
iteroselectively provide 1-bromo-4-methoxybenzene [14]. In contrast, using 1.5
equivalents of N,N-dibromo-p-toluenesulfonamide (TsNBr
2
), 1,3,5-tribromo-2-
methoxybenzene was prepared in 77% yield [15].
Methylation of benzene-1,3,5-triol (phlorogluctinol) is another example of
iteroselectivity [16].
OMe
Bromination
OMe
Br
OMe
Br
OMe
Br
OMe
Br
OMe
Br
OMe
Br
Br
Br
Br
OMe
Br
BrBr
OMe
Br
OMe
Br
Br
Br
Br
Br
Monobromination (i=1)
Dibromination (i=2)
Tribromination (i=3)
Regioselectivity
Iteroselectivity
Regioisomers
Iteromers
i corresponds to the number of iterations
OH
HO OH
OMe
HO
OH
OMe
HO OMe
MeOH, HCl
dioxane
70 °C, 4 h
62% yield
25% yield
Iteromers
2.28 One-pot Synthesis/Telescoping Process 25
Monoalkylation of primary amines is a challenging problem in traditional chem-
istry due to the formation of significant amounts of overalkylated side products. The
canonic case of monomethylation is the most difficult since nucleophilicity of the
amines increases according to the number of methyl groups without steric counter-
balance. For example, reaction of a primary amine 1 with MeI yields an inextricable
mixture of methylated products 2 and 3, along with the quaternary ammonium salt
4 as a major product [17]. In 2014, Julien Legros’ group developed an iteroselec-
tive monomethylation of primary amines by using MeOTf as methylation agent and
HFIP as solvent [18].
Monoprotection of diamine was a potential issue and often encountered in
medicinal chemistry. A Korean group of chemists developed an iteroselective
mono-Boc protection of diamine by using 1 equivalent of HCl and 1 equivalent of
Boc
2
O in MeOH-H
2
O [19]. For example, monoprotected ethylene diamine was pre-
pared in 87% yield by this method.
2.28 One-pot Synthesis/Telescoping Process
Chemists frequently employ one-pot synthesis, a method in which multiple
sequential reactions are conducted in a single reactor without isolating interme-
diates. This strategy enhances reaction efficiency by eliminating time-consuming
isolation and purification steps for intermediate compounds, thereby conserving
resources, reducing labor, and often enhancing overall reaction yields. One-pot syn-
thesis is particularly advantageous when intermediates are unstable under standard
workup conditions or prone to volatility during solution concentration, as it cir-
cumvents these challenges by maintaining reaction continuity within the controlled
environment of the reactor.
The telescoped process is to perform multiple transformations (including
quenching and other workups) without directly isolating intermediates. Telescoped
solutions of intermediates can be extracted, filtered (as long as the product remains
in the filtrate), and solvent exchanged, but the intermediate ultimately remains in
R NH
2
MeI
R NHMe
R NMe
2
R N
+
Me
3
I
–
+
+
1 2 3 4
Iteromers
MeOTf
HFIP
2 (52–96% selectivity)
1. HCl (1 eq.), MeOH
H
2
O, 0 °C - rt
87%
2. Diamine
3. Boc
2
O (1 eq.)
NHBoc
H
2
N
NH
2
H
2
N
2 General Terms and Concepts in Synthetic Organic Chemistry26
the solution and undergoes subsequent transformations. Therefore, the telescoped
process can be carried out in multiple pots.
Whether it’s the one-pot synthesis or the telescoped process, they are all within
the scope of process chemistry. These processes are based on successful step-by-step
synthesis or have defined reaction mechanisms.
An example of a one-pot synthesis is the preparation of molnupiravir starting
from cytidine [20]. Molnupiravir, which exerts its anti-SARS-CoV-2 effect through
lethal mutagenesis, was approved for emergency use authorization in the United
States. In 2022, Aisa and Shen’s group reported a one-pot process for preparing mol-
nupiravir from cytidine. In that process, three reactions were carried out in one
flask. It was not necessary to separate and purify intermediates 1 and 2.
The large-scale synthesis of an ampakine-type active pharmaceutical ingredient
(API) 5 is based on a telescoped regioselective double amidation [21]. Compound 5
O
N
HO
HO
OH
O
HO
O
O
N
NH
2
O
Cytidine
H
N(Me)
2
N
N
N
O
Evaporation of THF
solvent exchange to DCM
Isobutyric anhydride
Et
3
N, DMAP, 0–25 °C, 2 h
O
O
O
O
H
N
N
N
O
CH(NMe)
2
O
O
O
HO
OH
N
N
H
N
O
O
OH
1
2
DMF-DMA, THF
65 °C, 18 h
Evaporation of DCM
Hydroxylamine sulfate
70% aq. i-PrOH
78 °C, 18 h
Molnupiravir
63% crystallization yield
CH(NMe)
2
N(Me)
2
NO
2
OH
OH
O
O
N
O
N
OH
N
O
N
OH
HN
O
F
OH
HN
O
F
O
O
O
N
N
NO
2
OH
HN
O
F
O
N
N
OH
HN
O
F
O
HN
N
O
O
N
O
N
5
4
3
F
80 °C, 18 h
CDI (1.1 eq.)
25 °C, 9 h
Cyclopropanamine
(1.1 equiv)
25 °C, 1 h
3 steps
N
F
Overall yield from 3, 65%
DMSO/MeCN
CDI (1.1 eq.)
60 °C, 4 h
HO
2
C
CO
2
H
NO
2
CO
2
H
CO
2
H
NO
2
NO
2
NO
2
CO
2
H
NO
2
NH
2
2.29 Cascade Reaction 27
has been selected for clinical trials, which can increase AMPA receptor activation
and is therefore considered a “high-impact” AMPA receptor potentiator. In a pro-
cess of 5, the key intermediate 4 was prepared from compound 3 in the telescoped
process [21].
2.29 Cascade Reaction
A cascade reaction (also termed as domino reaction or tandem reaction)
is a process involving two or more sequential reactions, where each step is trig-
gered exclusively by functional groups generated in the preceding transformation.
Intermediates are not isolated, as each transformation occurs spontaneously under
consistent reaction conditions, with no additional reagents introduced after the
initial step. By strict definition, cascade reactions maintain unchanged parameters
(e.g., temperature, solvent, catalysts) throughout all stages.
In comparison, one-pot synthesis broadly encompasses conducting multiple
reactions consecutively in a single vessel without isolating intermediates, but
it allows modifications such as adding reagents or altering conditions (e.g., tem-
perature, pH) between steps. Thus, while all cascade reactions qualify as one-pot
processes, not all one-pot syntheses meet the stringent criteria of cascade reactions.
Although cascade sequences are predominantly intramolecular, they can proceed
intermolecularly, overlapping with multicomponent reactions when multiple
starting materials react in a single orchestrated sequence.
For example, an important class of complex multifunctional bicyclic lactams
(such as 3) were produced by a continuous flow process from aryl enamides. The
second stage is a thermo cascade process, which includes the ring-opening and
Diels–Alder reaction [22].
Ph
N
Bz
1
2,2ʹ-MeOTX (1%)
Blue LED
N
Ph
Bz
2
Heat
O
O
O
N
O
Ph
Bz
(+/–)-3
Photocycloaddition Thermo cascade reactions
Continuous flow process
Overall yield, 61%
20.4 g/h
S
O
OMe
MeO
2,2ʹ-MeOTX
(photo sensitizer)
HO
2
C