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342 Chemistry and Biology of Beta-Lactams
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FIGURE 11.6 The optimized and chemical geometries of the α- hydroxy-β-lactams.
SCHEME 11. 2 Synthesis of compound 3 and compound 4.
343The Effects of Dipole Moments on the Biological Activities of Diverse Beta-Lactams
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Table 11.2 shows the experimental ground-state dipole moment of eight α-hydroxy-beta-lactams. The
stereochemistry of compounds 1, 3, 5, and 7 has been determined to have cis-stereochemistry, and the
stereochemistry of compounds 2, 4, 6, and 8 has been determined to have trans-stereochemistry. Despite
the fact that the groups were positioned in either N1 or C3, a higher dipole moment was observed in
trans-molecules compared to cis-molecules.
A signicant difference was found between the dipole moment of the trans-molecule with the acetoxy
group at the C3 location and the compound with the hydroxyl group at the same location. According to
the AM1 calculation, the maximum dipole moment for trans-molecules with an OAc at the C3 location
and a phenyl at the N1 location is 6.32 D, for instance compound 2 which has an OAc at the C3 location and a phenyl at the N1 location. It was found that compound 4, which was characterized by a group
OAc at the C3 location and a group CO-phenyl at the N1 location, showed a dipole moment of 4.81 D.
Compound 8 showed a dipole moment of 2.43 D, and compound 6 had a dipole moment of 3.08 D. Also,
the cis-molecules showed a similar trend to the trans-molecules. It was found that the molecule with the
OAc group had a higher dipole moment than the cis-structure containing CO-phenyl and OH groups.
One of the best examples of this is molecule 7, which has the lowest value of dipole moment (1.78 D).
The dipole moments have been consistent in all four quantum mechanical studies (RM1, PM3, PM6, and
AM1), which is a noteworthy fact. The dipole moment data, which were derived from the PM3 calculations, were, however, found to be lower than the same data that were derived by other methods.
The results of the research indicated that trans-alpha-hydroxy-beta-lactams have a higher dipole
moment when compared with cis-alpha-hydroxy-beta-lactams. An energy-minimized 3D conguration
of the acetoxy isomers can be seen in cis-isomer 1. In this instance, consider that oxygen atoms in the
trans-compound 2 (5.1 Å), oxygen in the acetoxy functionality, and oxygen in the ring are compact to
each other (2.9 Å separation) (Figure 11.7 ). In cis-structures, due to the close proximity between the
TABLE 11.2
Dipole Moment Values of Compounds 1–8
Dipole Moment in Debye (D)
Compounds
1 6.33 5.63 5.59 5.62
2 7.07 5.37 6.40 6.32
3 2.69 2.43 2.58 2.63
4 5.25 4.38 4.51 4.81
5 2.77 2.25 2.58 2.59
6 3.26 2.20 3.04 3.08
7 1.98 1.78 2.05 1.78
8 2.79 2.26 2.48 2.43
PM6 PM3 RM1 AM1
FIGURE 11.7 Separation distance of oxygen atoms in stereoisomers.
344 Chemistry and Biology of Beta-Lactams
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molecules, there is the possibility of electronic repulsion and, as a result, a decrease in polarity as a result
of the overcrowding. Because of its molecular structure, it is expected that compound 4 will display the
highest dipole moment in the series. Due to the close placement of oxygen in the acetoxy group, oxygen
at C2 and oxygen at N1 (3.3 Å and 3.9 Å separation rates), there was a decrease in the dipole moment.
Eight α-hydroxy-beta-lactams were analyzed systematically using four semiempirical quantum
mechanical dipole moment calculations. The dipole moment of trans-compounds has been found to be
high despite the type of group present in the N1 and C3 centers of the compounds. As a result of the
quantum mechanical calculations, similar results were obtained as well.
11.4 Dipole Moment of Penicillins and Related β-Lactam Antibiotics
Among all of the classes of drugs that are used to treat human health problems, antibiotics are one of the
most benecial and useful ones. There is a wide range of benets associated with using these drugs, and
they are often used to treat infections caused by plants as well as animals.45 It is undeniable that betalactam antibiotics are among the most commonly used and one of the most frequently recommended
types of antibiotics out of all the antimicrobial agents.
Beta-lactam antibiotics can be categorized in a number of different ways, but penicillin derivatives
are possibly the most common type of beta-lactam antibiotic. As a member of the class of antibiotics
referred to as beta-lactams, penicillin G was the rst antibiotic to be discovered and used to treat a broad
spectrum of infections caused by bacteria. The discovery of penicillin was made by Alexander Fleming
in 1928.46 In terms of the basic geometry of penicillin, it can be described as being composed of the thiazolidine ring fused to the beta-lactam ring, with an aminoacyl side chain connected to this ring. There
is a hypothesis that states that in order for a compound to have effective antibacterial activity, it should
contain a ring of sufcient strain, with chances for the delocalization of electrons outside the ring, as well
as certain characteristics concerning its conformation. It has been shown that in the beta-lactam ring,
one of the geometrical elements involved in penicillin and compounds that are related to it are among
the most important geometrical elements of their antibacterial properties, as they have been shown to be
effective against most gram-negative and gram-positive bacteria.
Among the larger family of beta-lactam antibiotics, there has been no doubt that penicillins have been
the most signicant group of antibiotics since they were introduced in the early 1940s. Penicillin was the
rst drug that was proven to be effective in the treatment of a number of serious diseases such as syphilis
and Staphylococcus infections.49 There has been a considerable increase in the demand for penicillin
over the course of the last few decades.
50, 51
According to some scientic research, penicillin is capable
of binding to and inactivating the penicillin-binding protein in bacteria as well as inhibiting the crosslinking of peptidoglycans, which are vital for the formation of cell walls.52 This way, penicillin is able to
control bacteria by inhibiting the division of their cells in a way that inhibits their growth and reproduction. There are several metabolites of penicillin, but penicilloic acid and penilloic acid are considered
to be the most important.53 Among the many penicillin derivatives available today, there is only a small
percentage of them that have signicant biological properties, are less likely to cause side effects, and are
exposed to the environment in lower levels than other penicillin derivatives.
The relationship between the structure of penicillins and their biological activity has been extensively
studied in the course of the past few decades.
54, 55
When it comes to racemic antibiotics or optically active
antibiotics, it is possible that a minor change in the structure of these antibiotics can have an impact
on their medicinal activity. In order to be able to control biological activity, it is therefore necessary to
identify the fundamental causes of biological activity. In the pursuit of identifying factors that contribute
to the biological property of medicinally signicant compounds, researchers have proposed a variety of
theories in support of their hypothesis. There have been numerous studies that have shown that the value
of the dipole moment plays a signicant role in the therapeutic activity of both medicinally active and
inactive compounds.
Several studies have demonstrated a direct correlation between the dipole moment and the biological
activity of many compounds.
56–59
In a number of studies, it was shown that active compounds, such as
47, 48
345The Effects of Dipole Moments on the Biological Activities of Diverse Beta-Lactams
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tetraoxanes, quinazolinones, indolyl pyrimidines, and derivatives of quinolones, had a higher dipole
moment compared with compounds that were relatively inactive.
57, 60
By contrast, thiazolidines, phenothiazines, pyrazolopyridines, and derivatives of azoles, which have a small value of dipole moment, show
greater properties than their related compounds that have a higher dipole moment value.
59, 61, 62
A collection of four penicillin derivatives and three isomers of penicillin derivatives were considered in order to determine the dipole moment of the compounds. There are several types of penicillin
derivatives. For example, naturally occurring penicillins include penicillin V, which is phenoxymethylpenicillin, and penicillin G, which is benzylpenicillin; aminopenicillin, which is amoxicillin; and penicillinase-resistant penicillins, such as oxacillin. All of these derivatives are shown in Fig ur e 11.8 , along
with the optimized structures for each of these derivatives. In benzylpenicillin (1), the group at location
6β of the penam ring is phenylacetamido. There is a phenoxymethyl analogue of penicillin G known as
phenoxymethylpenicillin (2). Amoxicillin (3) contains a 2-amino-2-(4-hydroxyphenyl) acetamido group
substituting at location 6β of the penam ring.
Oxacillin (4) is a penicillin with an antistaphylococcal activity and contains a 5-methyl-3-phenylisoxazole-4-carboxamide group at the 6β location of the penam ring. Additionally, two other groups of normally employed molecules like thienamycin (6) and cephalosporin C (5) were considered for the study. In
any case, both of these molecules are closely related to penicillin, which is an important point to keep in
mind. A study of the cis- and trans-isomers of penicillin will also be undertaken in order to understand
the relationship between the structure of penicillin and its biological activity.
It is illustrated in Figu r e 11.9 that the stereoisomers of penicillin G in addition to their chemistry and
optimized structures are shown as well. A molecule 7 is an enantiomer of a molecule 1, and a molecule
9 and a molecule 8 are diastereomers of a molecule 1. Compounds 7 and 1 are now being considered cisisomers, while compounds 8 and 9 are being considered trans-isomers.
The SPARTAN 18 software package has been used in order to calculate the dipole moment of the compounds that were investigated. All the measurements were performed using a semiempirical quantum
chemistry method based on the equilibrium geometry at ground state, AM1, which is obtained by using
an integral approximation known as neglect of diatomic differential overlap (NDDO). Two-dimensional
drawing of each structure was created, and then the records were turned into their three-dimensional
forms by using the same software, and then a method of energy minimization was applied to all of the
structures.
There is an indication of the estimated value of dipole moment in Debye for each of the four derivatives of penicillin, thienamycin, as well as cephalosporin given in Table 11.3. It is important to note that
compounds 1–6 are all cis in nature. Compound 6 had a dipole moment value of 3.13 D, while molecules
1–5 had values ranging from 5.01 D to 6.72 D. Based on the literature that has been reviewed, compounds
1–5 have been shown in some studies to have a high level of antibacterial activity. As far as the biological
activity of compound 6 is concerned, so far there have been no published results on this subject. From
the analysis of the data obtained from this study, it appears that there is a direct relationship between
the biological properties of the compounds under consideration and their dipole moments. A drug with
a higher dipole moment value will have a greater potency when compared to a drug with a lower value.
In comparison to the other compounds, compound 4 exhibited the highest value of dipole moment with
a value of 6.72 D. There is a possibility that the higher value of the dipole moment could be attributed to
the fact that this molecule contains an isoxazole group in its side chain. Due to the isoxazole group in the
molecule, this may result in a better separation of charges in the molecule.
As shown in Table 11.4, the calculated dipole moment values for each stereoisomer of penicillin G
compounds are presented for comparison. On the basis of the results of the analysis, it appears that the
value of the dipole moment for compound 7 and compound 1 (cis-isomers) is larger than the value of
the dipole moment for compound 8 and compound 9 (trans-isomers). At the same time, the values of the
dipole moments in the two trans-isomers were almost similar to each other, while at the same time, the
values of the dipole moments in the two cis-isomers differed signicantly from one another in terms of
their dipole moments. The active isomer of penicillin G (1), cis-penicillin G (1), has a greater value of
dipole moment than its enantiomeric counterpart, the less active cis-penicillin G (7). Considering the
trans-isomers 8 and 9, both of them are inactive in the biological system.
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FIGURE 11.8 The optimized and chemical geometries of the four derivatives of penicillin, thienamycin, and cephalo-
sporin analogue.
FIGURE 11.9 The optimized and chemical geometries of the penicillin G isomers.
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TABLE 11.3
Calculated Dipole Moment Values of Derivatives of
Penicillin, Thienamycin, and Cephalosporin Analogue
Compounds Activity Dipole moment
1 Active 5.38 D
2 Active 5.01 D
3 Active 6.20 D
4 Active 6.72 D
5 Active 6.18 D
6 Inactive 3.13 D
347The Effects of Dipole Moments on the Biological Activities of Diverse Beta-Lactams
TABLE 11.4
Calculated Values of Dipole Moment Penicillin G Stereoisomers
Compounds Activity Dipole moment
1 Active 5.38 D
7 Inactive 4.49 D
8 Inactive 2.91 D
9 Inactive 3.08 D
Note: From the scientic literature, active and inactive wording is used. It
does not reect the quality of any research papers and the authors.
The results of this study have demonstrated that there is a direct correlation between the values of the
dipole moment of penicillin and its therapeutic activity, as well as a correlation between the values of
the dipole moment of related molecules. Four penicillin derivatives and penicillin G stereoisomers are
examined based on semiempirical calculations of their dipole moments. The dipole moments of active
compounds are observed to be high, usually above 5 D, which indicates that they have a large dipole
moment. All the compounds active in the study have one interesting fact in common: they are all cisisomers of the corresponding beta-lactams, which makes them very interesting compounds to study. In
comparison to compounds that are active, trans-compounds which are considered to be partially active
or inactive have been found to have a lower dipole moment than compounds that are active. As a result
of the ndings of this study, it can be concluded that determining the biological activity of cephalosporin
and thienamycin analogues highly depends on the values of dipole moments.
348 Chemistry and Biology of Beta-Lactams
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11.5 Dipole Moments of Polyaromatic Cytotoxic β-Lactams
Developing countries as well as developed nations have been experiencing a dramatic increase in cancer
cases, which is a deadly disease. Several cancer drugs are available on the market, as well as combinations of cancer drugs. Each one of them has its own set of side effects. As part of the list, there are chemotherapy drugs, hormone therapies, targeted cancer drugs, immunotherapy drugs, and bisphosphonates. A
point that needs to be made is that most of the anticancer drugs that are currently available are cytotoxic
to both normal and neoplastic cells. To develop new anticancer agents, it is essential that they have a high
degree of potency against cancerous cells, they have a low degree of toxicity toward normal cells, and
they possess unique mechanisms of action in order to be effective against cancerous cells. Our group has
conducted a systematic study by which different diverse organic compounds have been investigated in
terms of their anticancer activity in various different cell lines in vitro and in vivo through a systematic
63–77
study.
ing medicinally active compounds. There are a few green techniques, including organocatalysis, that
have been employed to prepare a number of compounds with anticancer properties.
that microwave-assisted reactions can be used to speed up the reaction process.
group has successfully demonstrated the use of tellurium for the synthesis of organic compounds that
are similar to a large number of natural anticancer agents, which have been shown to exert anticancer
effects.
efcacy in treating cancer. The success rate of chemotherapy has been observed to be declining for many
years now, which has led to an increase in the interest in developing beta-lactams as chemotherapeutic
agents in the past few years. In the course of the research, it was discovered that in order for future
development to be successful, we need to understand, quantify, and analyze the electronic interactions
between molecules both intramolecularly and intermolecularly in order to maximize efciency. In order
to achieve this goal, the ground-state dipole moments of beta-lactams have been measured as a step
toward relating the biological properties of these compounds. Moreover, the analysis also contributes
to understanding the inuence of substituents on lactam rings in terms of their inuence on the ring
structure. The study is the rst to identify a relationship between the dipole moments of a class of drugs
known as beta-lactams and the biological properties of these drugs. Consequently, this research could
certainly prove to be important as well as timely at the same time.
moments. Beta-lactam 1 contains a group of phenyls at position N1 of the lactam ring, an oxygen at
position C2, a group of acetoxy at position C3, and a group of phenyls at position C4, as shown in 1. As
a part of the study, other compounds such as compound 2, compound 3, compound 4, compound 5, and
compound 6 were also examined in order to investigate the effect of the substitution positions on these
compounds. The ring of 2 contains a naphthalene group at the N1 position of the ring, while the ring of
3 contains an anthracene group at the N1 location, the ring of 4 contains a phenanthrene group at the N1
location of the ring, and the ring of 5 contains a chrysene group at the N1 position of the ring. Lactam 6
is a cis-stereoisomer because the groups at N1 and C4 have been interchanged. Arrows are used in order
to indicate the direction in which electrons are moving in different structures.
SPARTAN 18 was used. Despite the fact that there are numerous successful methods, there are three
that are most commonly used: modied neglect of differential overlap (MNDO), AM1, and PM3. All
the models are based on the NDDO integral approximation, which is a well-known method. The NDDO
method has been developed into several kinds by reparametrizing the methods that already exist in this
area, resulting in the development of RM1 and PM6, which are two new versions of the NDDO method.
A total of ve methods were used for the purpose of calculating the dipole moment in this study.
plish this task, the PM3, PM6, RM1, AM1, and MNDO Hamiltonians must be changed. In order to
convert the structures from the 2D form to the 3D form, they were rst made in 2D format and then
converted to the 3D format using the same software, followed by an energy minimization procedure.
Researchers have found that theoretical approaches can be helpful when it comes to develop-
78–86
It has been found
87–102
Furthermore, our
103–114
There has been a lot of attention paid to beta-lactams over the past few years due to their potential
There are six different beta-lactams shown in Fig ure 11.10 that were used in the calculation of dipole
For the purpose of calculating the dipole moment for each compound, a software package named
All measurements are conducted at the ground state using equilibrium geometry, so in order to accom-
349The Effects of Dipole Moments on the Biological Activities of Diverse Beta-Lactams
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FIGURE 11.10 β-Lactam structure employed for calculation of dipole moments.
With the help of these strategies, it is also possible to obtain the stereochemically most stable structure
for each of the compounds shown in Fig u re 11.10.
A summary of the anticancer activity of these beta-lactams can be found in Tabl e 11. 5. A total of nine
different types of human cancer cell lines were tested, each of which had its own characteristics. Cells
TABLE 11.5
In Vitro Cytotoxicity of β-Lactams on Human Cancer Cell Lines (µM)
Cisplatin 1, 2, 3, 6 4 5
HT-29 16.99
BRO 7.66
SKOV 5.99
MCF-7 10.05
OVCAR 3.99
K-562 2.33
PC-3 4.66
HL-60 1.66
MDA-231 12.33
˃20
˃20
˃20
˃20
˃20
˃20
˃20
˃20
˃20
10.49 5.66
10.48 10.84
18.0 6.88
10.09 9.81
18.0 4.17
4.0 4.33
9.3 16.32
5.21 3.64
12.49 11.98
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from several types of cancer exist in the human body, including MCF-7 and MDA-231 cells from breast
cancer and BRO cells from melanoma tumors. SKOV and OVCAR cells come from ovarian cancers,
HT-29 cells come from colon cancer, PC-3 cells come from prostate cancer, and K-562 and HL-60 cells
come from blood cancers. There has already been discussion regarding its synthesis and anticancer
properties. Cisplatin has been used in this study as a reference since it is a chemotherapeutic agent used
to treat cancer. There was a nding in the study that 1, 2, 3, and 6 were not active against the cell lines
tested, and the maximum activities were observed at concentrations more than 20 µM/mL (a range that
is not considered to have an important effect).
Beta-lactams 4 and 5 have been demonstrated to be capable of inhibiting the growth of cancer cells in
a signicant number of studies. As far as certain cell lines are concerned, both of the lactam compounds
showed almost similar activity to cisplatin when it came to killing some cancer cells, such as the MCF-7
cancer cell line. The compounds displayed a higher activity against some cancer cells, for instance,
HT-29, than cisplatin, which means that they were more potent than cisplatin.
In Tabl e 11. 5, there is a description of the calculated ground-state dipole moments for the six betalactam compounds. It was found that compound 4 which has a phenanthrene group at the N1 position of
the ring and compound 5 which has a chrysene group at the N1 location of the ring exhibited the highest
dipole moment values, ranging from 5.14 D to 4.31 D, among the beta-lactams. As compared to other
methods of calculating dipole moments, the MNDO method provides the lowest values for the dipole
moment values, except for compound 2 and compound 6.
Following the anticancer activity data and the calculated dipole moment values, it can be concluded
that anticancer activity and dipole moment are directly related. It is noteworthy that only compound 4
and compound 5 showed activity against cancer compared to all the beta-lactam compounds tested in
this study. Additionally, their dipole moments were higher compared to the dipole moments of other
beta-lactam compounds in this study (above 4.3 D). It appears that the dipole moment of this compound
is strongly inuenced by the substituent group at the N1 location, which indicates that the location of the
substituent group affects the biological activity of this compound. It has been shown that the order of
aromatic rings at the location of N1 has a direct impact on the dipole moment. There is a decrease in the
polarity of a compound as more aromatic rings are arranged in a linear order (e.g., anthracene groups,
naphthalene groups). In beta-lactams, due to the angular arrangement of aromatic rings, such as the
chrysene group and the phenanthrene group, the charge separation between the atoms becomes greater,
which in turn makes the compounds more polar. A minimum structural requirement for a compound to
be cytotoxic is at least three aromatic rings with an angular conguration, as determined by anticancer
activity tests for chrysene and phenanthrene.
It is important to note that this explanation does not apply to compounds 5 and 6 because they are different in some way. Compounds 5 and 6 differ in stereochemistry at the ring junction when it comes to
stereochemistry, even though they are isomeric. Among them, there was a difference in terms of dipole
moment and anticancer activity. As compared to compound 5 which was active, compound 6 which was
inactive has a much smaller value of dipole moment than compound 5. Further conrmation has been
made of the fact that in the N1 position of the ring, there must be three aromatic rings that are positioned
in an angular conguration.
There is an important role played by the substituted beta-lactam ring in the variation of electron density in the system. A strong polar compound is formed by the angular arrangement of aromatic rings in
the chrysene group and the group of phenanthrene at the N1 of the ring. These groups act as powerful
electron-withdrawing groups that result in the compound being strongly polar.
In research, it has been demonstrated that there is a correlation between the dipole moment of betalactam compounds and the ability to ght cancer. To determine the dipole moments of six different
compounds, ve different dipole moment calculations were carried out on each compound. In active
compounds, there is a high dipole moment, which is above 4.3 D. Moreover, the study suggested that
it might be the substitutional group on the N1 of a beta-lactam ring that plays an important role in the
anticancer activity of this compound. In light of the results of these studies, it may be possible to design
and synthesize beta-lactams with higher anticancer activity in the future. Despite this, the present study
does not specically state that a higher value of dipole moment is what leads to a greater biological activity of beta-lactam molecules to a certain extent. In addition, beta-lactams have been found to exhibit a
351The Effects of Dipole Moments on the Biological Activities of Diverse Beta-Lactams
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relationship between their dipole moment and their anticancer activity, and this relationship has also
been demonstrated to be causal.
Due to the slow success rate of other chemotherapeutic agents, interest in beta-lactam-based anticancer drugs has increased. It is known that an optically active isomer of a racemic compound has a higher
and much more selective biological activity when compared to its racemic counterpart. Research on the
anticancer properties of racemic beta-lactams led to the development of analogues that are optically
active as well. For the rst time, our group reported optically active anticancer beta-lactams, and their
biological evaluation was conducted. It may be necessary to study beta-lactams’ physicochemical and
geometric properties using quantum mechanical or classical mechanical methods to understand their
anticancer activities. A theoretical study of those properties may be one way to explore the possibility of
expanding the knowledge of those properties in the real world.
The physicochemical and geometrical parameters including weight, total energy, solvation energy,
dipole moment, energy of the highest occupied molecular orbital, energy of the lowest unoccupied
molecular orbital, polar surface area, polarizability, number of hydrogen bond acceptors, number of
hydrogen bond donors, octanol–water partition coefcient, volume of the molecule, surface area, ovality,
ionization potential, energy gap, electron afnity, global hardness, electronegativity, global electrophilicity, chemical potential, and softness to identify a relationship with anticancer property of beta-lactams
were reported.
Fig u r e 11.11 shows two optically active beta-lactams that were used for the theoretical calculation in
the study. These beta-lactams have a chrysene group attached to the N1 location, oxygen at the C2 location, a group of acetoxy attached to the C3 location, and a group of phenyls attached to the C4 location
of the ring. It is important to note that both compounds are trans-beta-lactams, and compound (+)-2 is
the chiral isomer of the compound (−)-1.
To carry out the theoretical analysis of the compounds, SPARTAN 18, a software package, was used.
To calculate the results, ve different calculation methods have been employed, including quantum
mechanical methods and classical mechanical methods, to use a combination of these methods.
Generally, a semiempirical method can be described as a method that is based on quantum mechanics in some way. It is important to emphasize that these methods can be seen as modied versions of
the Hartree–Fock theory method. Because of the use of zero differential overlap approximation in the
calculation of these methods, they are much faster than their ab initio counterparts when compared to
the calculations using ab initio methods. In most cases, semiempirical methods such as MNDO, AM1,
and PM3 have been successful and are the most commonly used. The rst thing to note about all three
of these methods is that they are all based on the approximation of the NDDO integral. Through reparametrizing the existing NDDO methods, such as the RM1 and PM6, it has been possible to develop new
versions of NDDO methods that are more efcient. All of these methods have been used in this study
to calculate the dipole moment. All calculations were performed assuming equilibrium geometry at the
ground state by changing the RM1, PM3, PM6, MNDO, and AM1 Hamiltonians. All the structures were
created in 2D, and then their 3D structures were created using the same software.
Classical mechanics is considered to be the most fundamental method in molecular mechanics. The
use of classical force elds is known to be highly efcient in terms of calculating molecular energies,
in addition to other physicochemical parameters, by using this method. To calculate the dipole moment,
FIGURE 11.11 β-Lactam isomers used for the theoretical calculation.
N
OAc
N
O
O
OAc
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