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ABSTRACT
CHEMISTRY
ALOTAIBI, SAAD B.S. UMM AL-QURA UNIVERSITY, 2011
SYNTHESIS AND CHARACTERIZATION OF BENZALKONIUM SALTS AS
POTENTIAL ANTIMICROBIAL AGENTS
Committee Chair: Issifu I. Harruna, Ph.D.
Thesis dated July 2017
One of the most significant classes of industrial chemicals is benzalkonium salts.
Benzalkonium salts have application in large number of commercial products.
Benzalkonium salts enhance cationic surface activity and this particular property results
in the salts being useful biocides, detergents, and disinfectants. Their antimicrobial
activities depend on the structure of the side alkyl chain. For instance, long alkyl chains
of C12 were most effective against fungi, yeast, and ophthalmic solution, C14 were
effective against gram-positive bacteria, and C16 were effective against gram-negative
bacteria. To add them to the databank of structure activity relationships (SAR) of
benzalkonium salts, need for new compounds to kill (bactericide) or inhibit growth
(bacteriostatic) of bacteria and other microorganisms. In this study, quaternary salts of
benzalkonium compounds were synthesized with an alkyl chain length of C9. The salts
were characterized using 1H NMR, 13C NMR, mass spectrometry, and Fourier transform
infrared spectroscopy (FTIR).

SYNTHESIS AND CHARACTERIZATION OF BENZALKONIUM SALTS AS
POTENTIAL ANTIMICROBIAL AGENTS
A THESIS
SUBMITTED TO THE FACULTY OF CLARK ATLANTA UNIVERSITY
IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR
THE DEGREE OF MASTER OF SCIENCE
BY
SAAD ALOTAIBI
CHEMISTRY
ATLANTA, GEORGIA
JULY 2017
© 2017
SAAD ALOTAIBI
All Rights Reserved

ACKNOWLEDGEMENTS
I would like to express my deepest gratitude to my academic advisor, Professor
Issifu I. Harruna, in the Department of Chemistry, whose sound advice, patience, skills,
and understanding added significantly to my academic course. I would also like to
acknowledge him for lending me his vast knowledge and expertise in various areas
related to organic chemistry and his guidance in writing this thesis. I would also like to
convey my sincere appreciation to Dr. Huayang Li for his guidance while I was
conducting the laboratory procedure. My gratitude also goes to the committee members,
Dr. Khan and Dr. James Reed, for reviewing this research and providing valuable
recommendations. I would like to convey my gratitude to all members of the faculty of
the Department of Chemistry at Clark Atlanta University. Above all, I am grateful to Dr.
Cass D. Parker, the Chairman, for introducing me to organic chemistry and smoothing the
path to connecting the findings of my research project to real-life situations. I thank Dr.
Fidelis Onwumere, Chemistry Department, Federal University of Technology, Owerri,
Imo State, Nigeria for valuable discussions. I owe my heartfelt appreciation to my lovely
spouse, Fayruz Alotaibi, for her support and encouragement in my graduate studies with
organic chemistry. I acknowledge my mother and my father for their persistence and
advice throughout my graduatestudies. From the bottom of my heart, I would like to
thank the Saudi Arabian Cultural Mission for giving me this opportunity to achieve my
goal.
ii
TABLE OF CONTENTS
ACKNOWLEDGEMENTS ................................................................................................ ii
LIST OF FIGURES .............................................................................................................v
LIST OF TABLES ............................................................................................................ vii
LIST OF SCHEMES........................................................................................................ viii
LIST OF ABBREVIATIONS ............................................................................................ ix
CHAPTER
I. INTRODUCTION ...................................................................................................1
1.1 Gram-Positive and Gram-Negative Bacteria ...............................................2
1.2 Aim of the Research.....................................................................................4
II. BACKGROUND .....................................................................................................5
2.1 Antimicrobial Agents ...................................................................................5
2.2 Quaternary Ammonium Compounds ...........................................................6
III. EXPERIMENTS ....................................................................................................11
3.1 Materials ....................................................................................................11
3.2 Instrumentation ..........................................................................................11
3.2.1 Nuclear Magnetic Resonance Spectroscopy (NMR) ........................11
3.2.2 Fourier Transform Infrared Spectroscopy ........................................11
3.2.3 Mass Spectrometry............................................................................12
3.2.4 Procedure ..........................................................................................12
IV. RESULTS AND DISCUSSION ............................................................................16
4.1 Solubility ....................................................................................................19
4.2 Proton Nuclear Magnetic Resonance Spectroscopy (1H NMR) of 1B ......19
iii
CHAPTER
4.3 Carbon Nuclear Magnetic Resonance Spectroscopy (13C NMR) of 1B ....21
4.3.1 Fourier Transform Infrared Spectroscopy of 1B ..............................23
4.3.2 Mass Spectrometry of 1B..................................................................25
4.3.3 Proton Nuclear Magnetic Resonance Spectroscopy (1H NMR)

of 2B .................................................................................................26
4.4.3 Proton Nuclear Magnetic Resonance Spectroscopy (1H NMR)

of 3B..................................................................................................33
4.6 Proton Nuclear Magnetic Resonance Spectroscopy (1H NMR) of 4B ......41
4.6.1 Carbon Nuclear Magnetic Resonance Spectroscopy (13C NMR)

of 4B..................................................................................................43
4.7 Mass Spectrometry of 4B...........................................................................46
4.8 Summary of the Structural Differences between Compounds ...................48
V. CONCLUSION ......................................................................................................49
REFERENCES ..................................................................................................................50
iv
LIST OF FIGURES
Figure
1. Preparation of benzalkonium salts ............................................................................. 2
2. Gram-positive and gram-negative bacteria ................................................................3
3. Alkyldimethylbenzylammonium chloride structure ..................................................7
4. Didecyldimethlammonium chloride structure ............................................................7
5. 400 MHz 1H NMR spectrum of Compound 1B........................................................20
6. 400 MHz 13C NMR spectrum of Compound 1B ......................................................22
7. Fourier Transform Infrared spectrum for Compound 1B .........................................24
8. Mass spectrum of Compound 1B..............................................................................25
9. Mass spectrum of Compound 1B (vast observation) ...............................................25
13. Mass spectrum of Compound 2B (vast observation) ................................................32
16. 400 MHz 13C NMR spectrum of Compound 3B .......................................................37
17. Fourier Transform Infrared spectrum for Compound 3B ..........................................38
v
Figure
23. Mass spectrum of Compound 4B (vast observation) ................................................47
vi
LIST OF TABLES
Table
1. Solubility of the Compounds 1-4 at 25ºC .................................................................19
2. Proton NMR Data for Compound 1B .......................................................................21
3. Carbon 13 NMR Data for Compound 1B .................................................................23
4. Summary of FTIR Spectral Data for Compound 1B ................................................24
5. Mass Spectrum Data for Compound 1B ...................................................................26
6. Proton NMR Data of Compound 2B. .......................................................................28
8. Summary of FTIR Data for Compound 2B ..............................................................31
10. Proton NMR Data for Compound 3B. ......................................................................35
14. Proton NMR Data of Compound 4B. .......................................................................41
18. Summary of the Compounds Structures ...................................................................48
vii
LIST OF SCHEMES
Scheme
1. Preparation of Compound 1B ................................................................................16
viii
LIST OF ABBREVIATIONS
QAI Quaternary Ammonium Ionization
QACs Quaternary ammonium compounds
CMC Critical Micelle Concentration
NMR Nuclear Magnetic Resonance
FTIR Fourier Transform Infrared Spectroscopy
MS Mass Spectrometry
TLC Thin Layer Chromatography
SAR Structure Activity Relationships
ix
CHAPTER I
INTRODUCTION
Humans are frequently exposed to microbes (viruses, algae, fungi, and bacteria)
and microbial entities. Microbial entities can pose significant risks to human health.1
Microorganisms are ubiquitous, and irrespective of the condition of the environment
where they find themselves, they grow in certain conditions. Reduction of microorganism
population and the microbial entities thriving under non-sterile environments usually
necessitate the usage of antimicrobial agents.1
Different antimicrobial agents are employed for disinfection. Most belong to
either of two classes, either physical or chemical antimicrobial agents.2 Antimicrobial
agents are also used as preservatives for various industrial processes.2 Sanitizers or
disinfectants have different mechanisms of action and have different effects on various
microbial populations.3 Various microorganisms, such as bacteria, demonstrate different
levels of antimicrobial resistance.4 Bacterial spores provide resistance to many
environmental factors, including antibiotics; mycobacteria also demonstrate severe
antimicrobial resistance.4 Natural biofilms develop into bio-networks with a large range
of microbes entrenched in polysaccharide matrices which prevent the entry of active
antimicrobial components.5 It is important to destabilize or digest the biofilms to make
the microorganisms accessible to antimicrobials.5
1
2
The technique of Quaternary Ammonium Ionization (QAI) is often utilized to
produce various types of quaternary compounds, including benzalkonium halides.6 Alkyl
chains of certain lengths and quaternary salts are an integral part of an effective
antimicrobial agent. According to Kuča, the highest antimicrobial activity of quaternary
compounds is affected by alkyl chain length.7 Little or no antimicroorganism activity is
evident with carbon chains greater than or equal to 20 carbons.7
Quaternary salts, such as, benzalkonium chloride are bactericidal agents used to
kill gram-positive and non-spore forming bacteria (Figure 1).8 The quaternary salts
exhibit their antimicrobial activity through their alkyl chains by infiltrating the membrane
phospholipid layer leading to leakage.9 The magnitude of leakage and cell death are
higher in gram-positive bacteria than in gram-negative bacteria. As a result, in the
disinfection and sterilization of medical equipment, quaternary ammonium compounds
are used frequently.10 The N-benzyl-N,N-dimethylalkyl bromides were prepared by the
general method shown in Figure 1.8
N Ethanol N
R-Br Br
R
Reflux
Figure 1. Preparation of benzalkonium salts.
1.1 Gram-Positive and Gram-Negative Bacteria
Gram-positive bacteria stains purple on a gram stain test due to the peptidoglycan
layer (cell wall is 20-30 nm thick).11 Gram-positive bacteria takes up the crystal violet
dye used in the test, and then appears purple color when seen through a microscope.11
3
Gram-negative bacteria are those that appear pink under the microscope due to
their thin peptidoglycan (and 8-12 nm thick) layer that takes up minimal crystal violet
dye used in the gram staining process (Figure 2).11 Some examples of gram-positive
bacteria are Staphylococcus aureus, Bacillus anthracis, Clostridium tetani, and Viridans
mutans.12 On the other hand, gram-negative bacteria include Escherichia coli,
Helicobacter pylori, Cholera, Bordetella pertussis, and Enterobacter.12
Figure 2. Gram-positive and gram-negative bacteria.
An outer membrane is absent in gram-positive, but it is present in gram-negative.
The wall is smooth in gram-positive but wavy and comes in contact with plasma only at a
few site.12 The cell wall contains 70-80% peptidoglycan in gram-positive; it contains 10-
12% peptidoglycan in gram-negative.11 The lipid content in the wall is very low in gram-
positive and, it is 20-30% in gram-negative. Porin or hydrophilic channels are absent in

4
gram-positive, and it occurs in the outer membrane of gram-negative.12 The wall in gram-
positive contains teichoic acids and gram-negative contain lipopolysaccharides (LPS).11
Recently, there have been growing concerns over the phenomenon of
antimicrobial resistance by various microbes.13 Quaternary ammonium compounds are
one of the oldest and most used compounds to kill, prevent, or inhibit pathogenic
microbes.6 However, there are a few recent reports associating the quaternary compounds
with antimicrobial resistance.9 The current development of increased resistance to
quaternary compounds has sparked an increase in research for more effective and less
resistance antimicrobial compounds.9
1.2 Aim of the Research
The research aim is to synthesize and characterize new set of benzalkonium salts
as potential antimicrobial agents by selecting different secondary amines to compare the
polarity of the compounds. The polarity of these salts determines their potential to act as
a biocide on microorganism targets. The objective of this research is to synthesize and
characterize novel benzalkonium salts with C9 alkyl chain lengths with para-linkages as
potential antimicrobial agents.

CHAPTER II
BACKGROUND
2.1 Antimicrobial Agents
Biocide or antimicrobial pesticides refer to chemical agents that possess
preservative, disinfectant and antiseptic properties.14 According to DeQueiroz, biocides
such as pesticides, sanitizers and disinfectants protect non-living things (such as walls
and floors) from contamination by pathogenic microbes and disinfect or alleviate growth
of pathogenic microbes.15
Antimicrobial can be either chemical or physical agents or a combination of
both.9 Physical antimicrobial agents act by extreme environment methods, such as,
ionizing radiations, moist heat, low temperatures, ultraviolet radiation, dry heat, or
hydrostatic pressure.16 Antimicrobial agents are used to lower microbial population or to
achieve commercial sterilization.14 Chemical agents such as phenols, alcohols, and
quaternary compounds are commonly found in chemotherapeutic agents, sterilizers,
disinfectants, preservatives or antiseptics. Antiseptics are substances that preclude growth
or action of microorganisms in living tissues.13 Preservatives are substances that prevent
contamination by microorganisms and prolong product shelf life.13 A sanitizing agent is
added to a non-living object with the objective of reducing the microbial population to
levels satisfactory to public health.3 Sterilizing agents are chemical agents that have the
capability of destroying or eliminating all forms of microbes and their spores from an
5
6
environment or an object, including but not limited to bacillus species and their spores.3
Disinfectants are physical or chemical agents that are applied to non-living things to kill
or to permanently inactivate pathogenic microbes. However, disinfectants may not
necessarily destroy the microorganism spores.17
Antimicrobials differ in their chemical structure, as well as their mechanism of
action.17 Nevertheless, their eventual impact on the microorganism of interest,
particularly when lethal concentrations are used, may demonstrate some similarities.17
Most biocides have a broad spectrum of activity, though there are some specific biocides,
such as, 5-chloro-2-(2,4-dichlorophenoxy) phenol that are effective in obstructing lipid
synthesis by affecting the enol-acyl carrier protein reductase.14 Other sites that can be
targeted using antimicrobials include metabolic processes, cell wall components, and
components of the cytoplasm, such as mitochondria and ribosomes.18
2.2 Quaternary Ammonium Compounds
Quaternary ammonium compounds (QACs) obtained from ammonium salts
through alkylationare widely used as antimicrobials either singly or in combination with
other chemical agents.4 There are various phases in the historical development of QACs
which have led to various generations of quaternary salts.19 The first generation of QACs
were benzalkonium chlorides which were quaternary salts with particular alkyl
distributions and the compounds with long alkyl chains of C12 were most effective
against fungi, yeast, and ophthalmic solution, C14 were effective against gram-positive
bacteria, and C16 were effective against gram-negative bacteria.19,20

7
The second generation of the compounds was synthesized through substitution of
the aromatic rings in alkylbenzyldimethylammonium chlorides yielding C12, 50%; C14,
30%; C16, 17% and C18, 3%.21 The third generation of QACs are the dual quaternary
ammonium salts which are a combination of alkyldimethylbenzylammonium chloride
with various alkyl groups (Figure 3).22 The fourth generation of quaternary salts includes
the twin chain quaternary ammonium salts, such as, didecyldimethlammonium chloride
(Figure 4).22 According to Marek et al., the combination of dialkyldimethylammonium
chloride with benzalkonium chloride is the latest composite of QACs representing the
fifth generation of QACs.22 The fifth generation was described as more resistant to hostile
environments, less poisonous and more economical.22
Cl
Figure 3. Alkyldimethylbenzylammonium chloride structure.
Cl
N
Figure 4. Didecyldimethlammonium chloride structure.
The new combination of antimicrobial agents proved to be less toxic than the
standard benzalkonium chlorides.16 The new class of antimicrobials which is comprised
of polymeric quaternaries constitutes the sixth generation of quaternary salts.22 They have
been described as less toxic and safer in comparison to the previous classes of biocides.9
8
Recently, a seventh generation of QACs has been developed with a blend of bis-
quats components. The new blends have outstanding bactericidal properties against
Bactericides gingivalis, which is an anaerobic bacterium that causes oral infections. The
blend is also effective against Actinomyces viscosus, as well as, streptococcus species.9
Quaternary ammonium compounds can be classified into three major categories
based on the nature of functional groups; benzalkonium halides, dialkonium and
monoalkonium.23 Quaternary ammonium compounds are large molecules with a
molecular weight that usually ranges from 300 to 400 g/mole and are made up of two
distinguishable moieties: hydrophobic alkyl group and a positively charged central
nitrogen atom with strong affinity for water and maintain cationic nature at all pH
values.7 The two moieties impact on the chemical, as well as, the physical properties of
the quaternary ammonium compounds.7
Quaternary compounds have chemical and physical properties, which are proved
by their substitutes, mostly the alkyl length. The aqueous properties of the quaternary
salts reduce as the alkyl length or hydrophobicity of the molecule rises, similarly, the
critical micelle concentration (CMC) of the quaternary compounds, which affects the
efficacy of various surfactants associated applications declines with an increase in the
alkyl chain length of the molecule.19 The CMC of monoalkonium chlorides is
significantly higher than those of benzalkonium chlorides with an identical alkyl chain
length, indicating that the addition of a benzyl group to the polar head can also decrease
CMC.19 The lesser the value of the CMC, the more the efficacy of benzalkonium chloride
9
against pathogenic microbes.19 There are other physical and chemical properties that may
affect the nature of quaternary salts, such as organic carbon water partitioning.19
Quaternary compounds, such as the benzalkonium halides, are a significant group
of industrial chemicals.24 Due to their resilient cationic surface activity, QACs are
commonly used in domestic, health care, agriculture and industrial applications as
antiseptics, as well as, personal care products.24 Quaternary ammonium salts have also
found numerous applications as bioactive agents.24 They demonstrate a wide spectrum of
antimicrobial properties over a broad range of pH and are used in medical, household,
industrial and agricultural applications.7 In addition, quaternary ammonium salts are also
used as sanitizers, disinfectants, wood preservatives, fungicides, and pesticides at low
concentrations.7
Quaternary ammonium salts are also used as sanitizers for medical equipment in
hospitals and as skin antiseptics.7 Quaternary salts are commonly used as a combination
of two or more benzalkonium compounds differing only in the alkyl length.25
Mareket al.developed a set of novel mono-quaternary ammonium compounds
based on various pyridine-4-aldoxime salts.22 They determined the antimicrobial
properties and the toxicity of the set of the pyridine-4-aldoxine salts.22 They found that
C14 and C16 analogues were more effective against yeast, while C16 were totally non-
sensitive to filamentous fungi.22 However, none of the compounds evaluated had a higher
level of sensitivity in comparison to benzalkonium C12 analogue.22 In addition,
benzalkonium analogues also displayed less severe cytotoxicity in the cell viability test.8
In a different type of study, Debreceni, Meggyesi, and Mestyan examined dermal toxicity
10
of benzalkonium chlorides in combination with 2-propanol.26 They reported the spray
disinfectants made of the two compounds had the same level of effectiveness and safety
as conventional skin disinfectants.

CHAPTER III
EXPERIMENTS
3.1 Materials
Glycidyl 4-nonylphenyl ether 98% (C18H28O2), heptamethyleneimine 98%
(C7H15N), (methylamino)ethanol 98%(C3H9NO),1-(2-mydroxyethyl)piperazine98%
(C6H14N2O), hexamethyleneimine 99% (C6H13N), and benzyl chloride 99% (C7H7Cl)
were obtained from Sigma-Aldrich Chemical Company and used as received. Ethanol
drying: 500 ml of ethanol 99.5% in one necked bottom flask, 1g of magnesium metal
98% purity, and 0.5g of iodine (99.8 % pure) was refluxed at 78 °C for 6 hours. The
mixture was distilled and used immediately for the reaction.
3.2 Instrumentation
3.2.1 Nuclear Magnetic Resonance Spectroscopy (NMR)
Solution proton and carbon NMR (1H and 13C NMR) spectra were obtained using
a Bruker AVANCE 400 MHZ spectrometer with deuterated dimethyl sulfoxide (DMSO),
chloroform-d (CDCl3) as solvent, and tetramethylsilane as internal reference.
3.2.2 Fourier Transform Infrared Spectroscopy
A Perkin Elmer model 1600 Fourier Transmission Infrared spectrometer (FTIR)
was used. Samples (pellets) were prepared using KBr.
11
12
3.2.3 Mass Spectrometry
Mass spectrometry analyses were performed ona LTQ-Orbitrap Elite ETD mass
spectrometer (ThermoFisher) equipped with easy-spray electrospray ionization source
and nano-LC UltiMate 3000 high performance liquid chromatography system
(ThermoFisher)on a positive full-scan mode. The mass range was from 100-1000Da and
resolution was 60,000 at 400 m/z. Sample (5 uL) was delivered into the ion source
through a LC pump with a mobile phase as 90% methanol containing 0.1% formic acid at
4 uL/min flow rate.
3.2.4 Procedure
Glycidyl 4- nonylphenyl Ether with Heptamethyleneimine (Compound 1A)
In a single necked round bottom flask fitted with a condenser, glycidyl 4-
nonylphenyl ether (0.003 mol, 0.850 g) in dry ethanol (100 ml) was mixed with an
equimolar amount of the appropriate heptamethyleneimine of (0.003 mol, 0.379 g). The
nitrogen gas was used through the condenser for one hour, and the mixture was stirred in
the presence of magnetic stirrer for 24 hours. The reaction mixture was refluxed using an
oil bath to yield 1A.
Compound 1A with Benzyl Chloride (Compound 1B)
Benzyl chloride (0.003 mol, 0.345 g) was injected into the flask containing
compound 1A. The mixture was refluxed for 24 hours. Solvent was evaporated by using a
rotavap. Purification of crude compound 1B was achieved by column chromatography
using silica gel using a mixed solvent of ethyl acetate: acetonitrile: methanol: ammonium
hydroxide (ratio 6:1:1:1). Fractions of eluent were collected and analyzed by TLC. The
13
final product is viscous liquid and the yield is 71.94%. 1H NMR (CDCl3), δ (ppm): 6.86-
7.39 two aromatic rings, 0.89-2.56 the long alkyl chain (C9H19), 1.64-3.47 the secondary
amine. 3.55-4.60 of (CH four protons in between oxygens and nitrogen atoms). 13C NMR
(CDCl3), δ (ppm): 113.76-156.51 two aromatic rings, 14.09-36.98 the long alkyl chain
(C9H19), 37.41-62.33 the secondary amine. 65.71-72.70 39 of the methylene carbons
resonances in between two oxygens and nitrogen atoms were downfield.
Glycidyl 4- nonylphenyl Ether with 2-(Methylamino) ethanol (Compound 2A)
equimolar amount of the appropriate 2-(methylamino)ethanol of ( 0.003 mol, 0.250 g).
Nitrogen gas was used through the condenser for one hour, and the mixture was stirred in
compound 2A. The mixture was refluxing for 24 hours. Solvent was evaporated by using
a rotavap. Purification of crude compound 2B was achieved by column chromatography
on silica gel using a mixed solvent system ethyl acetate: acetonitrile: methanol:
ammonium hydroxide (ratio 6:1:1:1). Fractions of eluent were collected and analyzed by
TLC. The final product is viscous liquid and the yield is 65.17%. 1H NMR (CDCl3), δ
(ppm): 6.65-7.28 two aromatic rings, 0.41-2.11 the long alkyl chain (C9H19), 2.22-3.45
the secondary amine. 3.90- 4.01 of (CH four protons in between oxygens and nitrogen
atoms). 13C NMR (CDCl3), δ (ppm): 114.14-156.87 two aromatic rings, 17.64-31.73 the
14
long alkyl chain (C9H19), 33.36-56.42 the secondary amine. 60.60-67.39 of the methylene
carbons resonances in between two oxygens and nitrogen atoms were downfield.
Glycidyl 4-nonylphenyl Ether with 1-(2-Hydroxyethyl) piperazine (Compound

3A)
equimolar amount of the appropriate 1-(2-hydroxyethyl)piperazineof (0.003 mol, 0.380).
Nitrogen gas was flushed through the condenser for one hour, and the mixture was stirred
in the presence of magnetic stirrer for 24 hours. The reaction mixture was refluxed using
an oil bath to yield 3A.
compound 3A. The mixture was refluxed for 24 hours. Solvent was evaporated by using
rotavap. Purification of crude compound 3B was achieved by column chromatography on
Silica gel with the ratio of solvents ethyl acetate: acetonitrile: methanol: ammonium
hydroxide (6:1:1:1). Fractions of eluent were collected and analyzed by TLC. The final
product is viscous liquid and the yield is 70.81%. 1H NMR (CDCl3), δ (ppm): 6.85-7.34
two aromatic rings, 0.96-2.57 the long alkyl chain (C9H19), 2.58-3.40 the secondary
amine. 3.67-3.99 of (CH four protons in between oxygens and nitrogen atoms). 2.60-3.63
the two protons CH which attached to the nitrogen moved downfield due to the effect of
the withdrawing group. 13C NMR (CDCl3), δ (ppm): 113.62-156.30 two aromatic rings,
13.79-34.79 the long alkyl chain (C9H19), 34.79-52.93 the secondary amine. 60.68-70.17
the methylene carbons resonances in between two oxygens and nitrogen atoms were
15
downfield. 57.85-59.56 the two carbons CH which attached to the nitrogen moved
downfield due to the effect of the withdrawing group.
Glycidyl 4- nonylphenyl Ether with Hexamethyleneimine (Compound 4A)
equimolar amount of the appropriate hexamethyleneimineof (0.003 mol, 0.356 g). The
nitrogen gas was used through the condenser for one hour, and the mixture was stirred in
Benzyl chloride (0.003 mol, 0.345 g) was injected in the flask containing
compound 4A. The mixture was refluxing for 24 hours. Solvent was evaporated by using
rotavap. Purification of crude compound 4B was achieved by column chromatography on
Silica gel with the ratio of solvents ethyl acetate: acetonitrile: methanol: ammonium
hydroxide (6:1:1:1). Fractions of eluent were collected and analyzed by TLC. The final
product is viscous liquid and the yield is 72.82%. 1H NMR (CDCl3), δ (ppm): 6.87-7.38
two aromatic rings, 0.51-2.55 the long alkyl chain (C9H19), 1.65-3.56 the secondary
amine. 3.67-4.53 of (CH four protons in between oxygens and nitrogen atoms). 13C NMR
(CDCl3), δ (ppm): 113.97-156.55 two aromatic rings, 14.11-36.98 the long alkyl chain
(C9H19), 30.07-66.17 the secondary amine. 62.77-76.79 of the methylene carbons
resonances in between two oxygens and nitrogen atoms were downfield.

CHAPTER IV
RESULTS AND DISCUSSION
The reaction scheme to compound 1B is presented in Scheme 1. Upon
forming 1A, the addition of benzyl chloride results in a Menschutkin type reaction to
yield 1B; 1B was isolated by TLC and characterized by 1H, 13C NMR, FTIR, and
mass spectroscopy.
C9H19 OH
Ethanol
O NH N O C9H19
Reflux/24hrs
O
Compound 1A
CH2Cl
Reflux/24hrs
Cl
OH
N O C9H19
Compound 1B
Scheme 1. Preparation of Compound 1B.
16
17
mass spectrometry.
C9H19 OH
H HO
N OH Ethanol
H3C N O C9H19
O Reflux/24hrs H3C
O
Compound 2A
CH2Cl
Reflux/24hrs
Cl OH
HO
N O C9H19
H3C
Compound 2B
mass spectrometry.
18
C9H19 H OH
N
Ethanol
N N O C9H19
O Reflux/24hrs HO
N
O
Compound 3A
OH
CH2Cl
Reflux/24hrs
OH
Cl
N N O C9H19
HO
Compound 3B
mass spectrometry.
OH
C9H19
Ethanol
N O C9H19
O Reflux/24hrs
O N
H
Compound 4A
CH2Cl
Reflux/24hrs
Cl OH
N O C9H19
Compound 4B

19
4.1 Solubility
The compounds were characterized by solubility, are soluble at room temperature
(25°C) in polar solvents such as, ethanol, dimethylformamide, isopropanol, and ethyl
acetate. Also, they are insoluble in nonpolar solvents such as diethyl ether, chloroform,
hexane, and benzene. The solubility results are summarized in Table 1.
Table 1. Solubility of the Compounds 1-4 at 25°C
Compound Ethanol Dimethylformamide Isopropanol Ethyl Acetate
1B + + + +
2B + + + +
3B + + + +
4B + + + +
Compound Diethyl Ether Chloroform Hexane Benzene
1B - - - -
2B - - - -
3B - - - -
4B - - - -
+ = Soluble, - = Insoluble
4.2 Proton Nuclear Magnetic Resonance Spectroscopy (1H NMR) of 1B
The 400 MHz 1H NMR spectrum of 1B is displayed in Figure 5, and the peak
assignments are presented in Table 2. The chemical shifts of the two aromatic rings
appear between 6.86 and 7.39 ppm. The assignment of 1H NMR was compared to the
simulated spectrum generated using ChemDraw®software. The spectrum showed the

20
long alkyl chain (C9H19) at 0.89 - 2.56 ppm. The secondary amine appeared at the range
of 1.64-3.47 ppm. Because the presence of two oxygens and nitrogen close to (CH four
protons), they were shifted more downfield between 3.55-4.60 ppm.
Figure 5. 400 MHz 1H NMR spectrum of Compound 1B.

21
Table 2. Proton NMR Data for Compound 1B
27 28
Cl-
OH
26 29 12 13
15 9 7 5 3
1
25
N+ O
16 14
8 6 4 2
24 23 17
11 10
22 18
21 19
20
Structure Proton Number Chemical Shift (ppm) Remark
C9H19 1-9 0.89-2.56 Alkyl Chain
b a
a b
10-13 and 18-22 6.86-7.39 Two Aromatic Rings
23-28 1.64-3.47 Secondary Amine

NH
CH2 14-17 3.55-4.60
4.3 Carbon Nuclear Magnetic Resonance Spectroscopy (13C NMR) of 1B
The 400 MHz 13C NMR spectrum of 1B is displayed in Figure 6, and the peak
appear between 113.76 and 156.51 ppm. The assignment of 13C NMR was compared to
the simulated spectrum generated using ChemDraw® software. The long alkyl chains
appeared between 14.09-36.98 ppm. Quaternary amine showed in the range of 37.41-
62.33 ppm. Carbon of (CH2) was shifted more downfield between 65.71-72.70 ppm. The
proton and the carbon NMR spectra confirm the structure of 1B.
22
Figure 6. 400 MHz 13C NMR spectrum of Compound 1B.

23
Table 3. Carbon 13 NMR Data for Compound 1B
27 28
Cl-
OH
26 29 12 13
15 9 7 5 3
1
+
25
N O
16 14
8 6 4 2
24 23 17
11 10
22 18
21 19
20
Structure Carbon Number Chemical Shift (ppm) Remark
C9H19 1-9 14.09-36.98 Alkyl Chain
b a
a b
10-13 and 18-22 113.76-156.51 Two Aromatic
Rings

NH
CH2 14-17 65.71-72.70
4.3.1 Fourier Transform Infrared Spectroscopy of 1B
FTIR shows the appropriate presence of the functional groups of compound 1B
and is illustrated in Figure 7 and Table 4. The broad OH appeared at 3416 cm-1. Alkane C-
H stretch appeared at 2956 cm-1. Tertiary amine showed a sharp band at 1377 cm-1. The
aromatic C=C appeared at 1610 cm-1, and C-O band showed at 1097 cm-1. The
monosubstituted benzene absorption appeared at 749 cm-1. Also, the para substituted
benzene peak appeared at 827 cm-1.

24
Figure 7. Fourier Transform Infrared spectrum for Compound 1B.
Table 4. Summary of FTIR Spectral Data for Compound 1B
Functional Group Wavenumber (cm-1) Intensity
OH 3416 Broad
Alkane C-H 2956 Stretch
Tertiary amine 1377 Sharp
Aromatic C=C 1610 Weak
C-O 1097 Strong
749 Monosubstituted
827 Para Substituted

25
4.3.2 Mass Spectrometry of 1B
The mass spectrometry showed the molecular ion peak M+ of compound 1B,
which has the molecular formula of C32H50NO2+ at 480.4 M/z. The base peak appeared at
390.3 M/z and has a molecular formula of C25H43NO2+. Also, loss of phenyl radical
detected by the mass at 404.4M/z is observed, and has molecular formula of C26H46NO2+.
The Mass Spectra are presented in Figures 8 and 9, and Table 5.
Figure 8. Mass spectrum of Compound 1B.
Figure 9. Mass spectrum of Compound 1B (vast observation).

26
Table 5. Mass Spectrum Data for Compound 1B
Fragment M/z Remark
.
OH 480.4 Molecular ion peak M+
N O C9H19
.
OH 390.3 Base peak
N O C9H19
.
OH 404.4 Loss of Phenyl radical
N O C9H19
4.3.3 Proton Nuclear Magnetic Resonance Spectroscopy (1H NMR) of 2B
The 1H NMR 2B is displayed in Figure 10 and the peak assignments are presented
in Table 6. The chemical shifts of the two aromatic rings appear between 6.65 and 7.28
ppm. The assignment of 1H NMR was compared to the simulated spectrum generated
27
using ChemDraw® software. The figure showed the long alkyl chain (C9H19) at 0.41-
2.11 ppm. The secondary amine appeared in the range of 2.22-3.45 ppm. The presence of
two oxygens and nitrogen close to (CH2 four protons), they were shifted more downfield
between 3.90- 4.01 ppm.

28
OH
24 12 13
HO Cl-
15 9 7 5 3
1
N+ O
16 14
8 6 4 2
23 17
11 10
22 18
21 19
20

C9H19 1-9 0.41-2.11 Alkyl Chain
b a
a b
10-13 and 18-22 6.65-7.28 ppm Two Aromatic Rings
23-24 2.22-3.45 ppm Secondary Amine

NH
CH2 14-17 3.90-4.01 ppm
The 13C NMR spectrum of 2B is displayed in Figure 11, and the peak assignments
are presented in Table 7. The chemical shifts of the two aromatic rings appear between
114.14 and 156.87 ppm. The assignment of 13C NMR was compared to the simulated
spectrum generated using ChemDraw® software. The long alkyl chains appeared
between at 17.64-31.73 ppm. Quaternary amine resonance peaks were between 33.36-
56.42 ppm. The four methylene carbon appeared downfield between 60.60-67.39 ppm.
The NMR spectra results support the formation of compound 2B.

29

30
OH
24 12 13
HO Cl-
15 9 7 5 3
1
N+ O
16 14
8 6 4 2
23 17
11 10
22 18
21 19
20
C9H19 1-9 17.64-31.73 Alkyl Chain
b a
a b

NH
CH2 14-17 60.60-67.39
FTIR absorption peaks are consistent with the functional groups of compound 2B.
The broad OH is appeared at 3303 cm-1. Alkane C-H stretch appeared at 2959 cm-1.
Tertiary amine showed a sharp band at 1377 cm-1. The aromatic alkene C=C appeared at
1608 cm-1, and C-O band clearly appeared at 1186 cm-1. The monosubstituted benzene
absorption appeared at 703 cm-1. Also, the para substituted benzene appeared at 828 cm-1
as confirmed and reported in Figure 12, and Table 8.

31
Table 8. Summary of FTIR Data for Compound 2B
OH 3303 Broad
C-O 1186 Strong
703 Monosubstituted

32
The mass spectrometry showed the molecular ion peak M+ of compound 2B at
428.3 M/z, which has the molecular formula of C27H42NO3+. In addition, the base peak
appeared at 352.2M/z, and has the molecular formula of C21H38NO3+. Also, loss of
phenyl radical detected by the mass at 338.3 M/z, and has the molecular formula of
C20H35NO3+. They are illustrated in Figure 13, Figure 14, and Table 9.

33
Fragment M/z Remark
.
OH
HO
N O C9H19 428.3 Molecular ion peak M+
.
352.2 Phenyl radical
OH
HO
N O C9H19
.
338.2 Loss of benzyl group
OH
HO
N O C9H19
4.4.3 Proton Nuclear Magnetic Resonance Spectroscopy (1H NMR) of 3B
The 1H NMR spectrum of 3B is displayed in Figure 15 and the peak assignments
6.85 and 7.34 ppm. The assignment of 1H NMR was compared to the simulation
spectrum generated using ChemDraw® software.

34

35
25 26
OH
28 12 13
HO Cl- 9 7 5 3
1
N N+ 15 O
27 16 14
17 8 6 4 2
24 23 11 10
22 18
21 19
20
C9H19 1-9 0.49-2.57 Alkyl Chain
b a
a b

HN NH
CH2 14-17 3.67-3.99
CH2 27-28 2.60-3.63
The spectrum showed peaks for the long alkyl chain (C9H19) between 0.96-2.57
ppm. The secondary amine appeared between the ranges of 2.59-3.40 ppm. Because the
presence of two oxygens and nitrogen close to (CH four protons), they were shifted more
downfield between 3.66-3.99 ppm. Also, the two protons which attached to the nitrogen
moved downfield (2.60-3.63 ppm) due to the effect of the withdrawing group.
36
The 13C NMR spectrum of 3B is displayed in Figure 16, and the peak assignments
113.62 and 156.30 ppm. The assignments of 13C NMR was compared to the simulated
spectrum generated using ChemDraw® software. The long alkyl chains show resonances
between 13.79-34.79 ppm. Quaternary amine peaks is observed in the range of 34.79-
52.93 ppm. The methylene carbons resonances were downfield between 60.68-70.17
ppm. Also, the carbon peak of (CH2) moved downfield (57.85-59.56 ppm) due to the
withdrawing group. The NMR spectral data is consistent with the structure of compound
3B.
25 26
OH
28 12 13
HO Cl- 9 7 5 3
1
+
N N 15 O
27 16 14
17 8 6 4 2
24 23 11 10
22 18
21 19
20
Structure Carbon Number Chemical Shift (ppm) Remark

C9H19 1-9 13.79-34.79 Alkyl Chain
b a
HN NH
CH2 14-17 60.68-70.17
CH2 27-28 57.85-59.56

37

38
FTIR absorption peaks are consistent with the functional groups of compound 3B
and illustrated in Figure 17 and Table 12. The broad OH is appeared at 3335 cm-1. Alkane
C-H stretch appeared at 2960 cm-1. Tertiary amine showed a sharp band at 1377 cm-1.
The aromatic C=C appeared at 1609 cm-1, and C-O band showed at 1096 cm-1. The
monosubstituted benzene absorption appeared at 762 cm-1. Also, the para substituted
benzene appeared at 828 cm-1.

39
OH 3335 Broad
C-O 1096 Strong
762 Monosubstituted
The mass spectrometry showed the molecular ion peak M+ of compound 3B,
which has molecular formula of C31H49N2O3+ at 497.4M/z. The base peak appeared at
407.3 M/z, and has a molecular formula of C24H42N2O3+. Also, loss of benzyl group
addicted by the mass at 421.3 M/z is observed, and has molecular formula of
C25H45N2O3+. The Mass Spectra are presented in Figure 18 and Table 13.
40
Fragment M/z Remark

.
OH
HO
N N O C9H19
497.4 Molecular ion peak M+
.
OH
HO
N N O C9H19
407.3 Base peak
.
OH
HO
N N O C9H19
421.3 Loss benzyl group
41
4.6. Proton Nuclear Magnetic Resonance Spectroscopy (1H NMR) of 4B
The 400 MHz 1H NMR spectrum of 4B is displayed in Figure 19 and the peak
appear between 6.87 and 7.38 ppm. The assignment of 1H NMR was compared to the
simulation spectrum generated using ChemDraw® software. The spectrum showed the
long alkyl chain (C9H19) at 0.51-2.55 ppm. The secondary amine appeared at the range
of1.65-3.56 ppm. Because the presence of two oxygens and nitrogen close to (CH four
protons), they were shifted more downfield between 3.67-4.53 ppm.
OH
27 28 12 13
Cl- 15 9 7 5 3
1
26 N+ O
16 14
17 8 6 4 2
25
23 11 10
24
22 18
21 19
20
C9H19 1-9 0.51-2.55 Alkyl Chain
b a
a b
NH
23-28 1.65 -3.56 Secondary Amine
CH2 14-17 3.67-4.53

42

43
4.6.1 Carbon Nuclear Magnetic Resonance Spectroscopy (13C NMR) of 4B
The 13C NMR spectrum of 4B is displayed in Figure 20 and the peak assignments
113.97 and 156.55 ppm. The assignments of 13C NMR was compared to the simulated
spectrum generated using ChemDraw® software.

44
OH
27 28 12 13
Cl- 15 9 7 5 3
1
+
26 N O
16 14
17 8 6 4 2
25
23 11 10
24
22 18
21 19
20

C9H19 1-9 14.11-36.98 Alkyl Chain
b a
a b
NH 23-24 30.07-66.17 Secondary Amine
CH2 14-17 62.77-76.79
The long alkyl chains show resonances between 14.11-36.98 ppm. Quaternary
amine peaks are observed in the range of 30.07-66.17 ppm. The four methylene carbon of
appeared downfield between 62.77-76.79 ppm. The spectra support the formation of
compound 4B.
FTIR absorption peaks are consistent with the functional groups of compound 4B.
The broad OH is appeared at 3419 cm-1. Alkane C-H stretch appeared at 2926 cm-1.
Tertiary amine showed a sharp band at 1377cm-1. The aromatic alkene C=C appeared at
1609 cm-1, and C-O band clearly appeared at 1186 cm-1. The monosubstituted benzene
45
absorption appeared at 731 cm-1. Also, the para substituted benzene appeared at 827 cm-1
and is presented in Figure 21 and Table 16.
OH 3419 Broad
C-O 1186 Strong
731 Monosubstituted

46
4.7 Mass Spectrometry of 4B
The mass spectrometry showed the molecular ion peak M+of compound 4B at
466.4 M/z, and has the molecular formula of C31H48NO2+. In addition, the base peak
appeared at 376.3 M/z, and has molecular formula of C24H41NO2. They are illustrated in
Figure 22, Figure 23, and Table 13.

47
Fragment M/z Remark

.
OH
N O C9H19 466.4 Molecular ion peak M+
.
OH
376.3 Base Peak
N O C9H19
48
4.8 Summary of the Structural Differences between Compounds
The compounds have different structures and modified by secondary amines
which are summarized in Table 18.
Table 18. Summary of the Compounds Structures
Compounds Structure Modify
1B OH
Cl-
N+ O C9H19 NH
2B OH
HO Cl-
N+ O C9H19 HO
NH
Compounds Structure Modify
3B Cl- OH
HO
N N+ O C9H19 HO
N NH
4B OH
Cl-
N+ O C9H19
NH
CHAPTER V
CONCLUSION
Benzalkonium salts were synthesized and characterized using 1H NMR, 13C
NMR, FTIR, and mass spectroscopic techniques. The compounds are soluble in polar
solvents, such as, ethanol, dimethylformamide, isopropanol, ethyl acetate, and insoluble
in nonpolar solvents such as, diethyl ether, chloroform, hexane, and benzene. 1HNMR
and 13CNMR spectra showed the aromatic rings, alkyl chain, and tertiary amine peaks. In
addition, FTIR showed all the expected functional groups in the compounds. Mass
spectrometry showed molecular ion peaks M+, base peaks, loss of benzyl group, and
dehydration of the compounds. Future work may include preparing optically pure
compounds, studying their optical rotation, and detailed antimicrobial tests. Also, similar
compounds with C8 and C10alkyl chain analogs may be prepared in order to determine
any odd-even effects.
49
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ABSTRACT

ALOTAIBI, SAAD B.S. UMM AL-QURA UNIVERSITY, 2011

SYNTHESIS AND CHARACTERIZATION OF BENZALKONIUM SALTS AS

POTENTIAL ANTIMICROBIAL AGENTS

Committee Chair: Issifu I. Harruna, Ph.D.

Thesis dated July 2017

One of the most significant classes of industrial chemicals is benzalkonium salts.

Benzalkonium salts have application in large number of commercial products.

bacteria. To add them to the databank of structure activity relationships (SAR) of

(bacteriostatic) of bacteria and other microorganisms. In this study, quaternary salts of

infrared spectroscopy (FTIR).

POTENTIAL ANTIMICROBIAL AGENTS

SUBMITTED TO THE FACULTY OF CLARK ATLANTA UNIVERSITY

IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR

THE DEGREE OF MASTER OF SCIENCE

All Rights Reserved

I would like to express my deepest gratitude to my academic advisor, Professor

and understanding added significantly to my academic course. I would also like to

recommendations. I would like to convey my gratitude to all members of the faculty of

Fidelis Onwumere, Chemistry Department, Federal University of Technology, Owerri,

advice throughout my graduatestudies. From the bottom of my heart, I would like to

LIST OF FIGURES .............................................................................................................v

LIST OF TABLES ............................................................................................................ vii

LIST OF SCHEMES........................................................................................................ viii

LIST OF ABBREVIATIONS ............................................................................................ ix

1.1 Gram-Positive and Gram-Negative Bacteria ...............................................2

1.2 Aim of the Research.....................................................................................4

II. BACKGROUND .....................................................................................................5

2.1 Antimicrobial Agents ...................................................................................5

2.2 Quaternary Ammonium Compounds ...........................................................6

III. EXPERIMENTS ....................................................................................................11

3.1 Materials ....................................................................................................11

3.2 Instrumentation ..........................................................................................11

3.2.1 Nuclear Magnetic Resonance Spectroscopy (NMR) ........................11

3.2.2 Fourier Transform Infrared Spectroscopy ........................................11

3.2.3 Mass Spectrometry............................................................................12

3.2.4 Procedure ..........................................................................................12

IV. RESULTS AND DISCUSSION ............................................................................16

4.1 Solubility ....................................................................................................19

4.2 Proton Nuclear Magnetic Resonance Spectroscopy (1H NMR) of 1B ......19

4.3 Carbon Nuclear Magnetic Resonance Spectroscopy (13C NMR) of 1B ....21

4.3.1 Fourier Transform Infrared Spectroscopy of 1B ..............................23

4.3.2 Mass Spectrometry of 1B..................................................................25

4.3.3 Proton Nuclear Magnetic Resonance Spectroscopy (1H NMR)

4.4 Carbon Nuclear Magnetic Resonance Spectroscopy (13C NMR) of 2B ....28

4.4.1 Fourier Transform Infrared Spectroscopy of 2B ..............................30

4.4.2 Mass Spectrometry of 2B..................................................................32

4.4.3 Proton Nuclear Magnetic Resonance Spectroscopy (1H NMR)

4.5 Carbon Nuclear Magnetic Resonance Spectroscopy (13C NMR) of 3B ....36

4.5.1 Fourier Transform Infrared Spectroscopy of 3B ..............................38

4.5.2 Mass Spectrometry of 3B..................................................................39

4.6 Proton Nuclear Magnetic Resonance Spectroscopy (1H NMR) of 4B ......41

4.6.1 Carbon Nuclear Magnetic Resonance Spectroscopy (13C NMR)

4.6.2 Fourier Transform Infrared Spectroscopy of 4B ..............................44

4.7 Mass Spectrometry of 4B...........................................................................46

4.8 Summary of the Structural Differences between Compounds ...................48

1. Preparation of benzalkonium salts ............................................................................. 2

2. Gram-positive and gram-negative bacteria ................................................................3

3. Alkyldimethylbenzylammonium chloride structure ..................................................7

4. Didecyldimethlammonium chloride structure ............................................................7