Download Title: Nuclear Magnetic Resonance (NMR

Title: Nuclear Magnetic Resonance (NMR) Spectroscopy: A Comprehensive Review
Title: Nuclear Magnetic Resonance (NMR) Spectroscopy: A Comprehensive Review
Running title: NMR-A review
Abstract
Nuclear Magnetic Resonance (NMR) is one of the most significant diagnostic tools that
have been developed in the past few decades. A broad range of biological and nonbiological samples ranging from an individual cell to organs and tissues can be
investigated through NMR. Many aspects of this technique are still under research and
many functions of the NMR are still pending better understanding and acknowledgement.
Therefore, this review is aimed at providing a general overview of the main principles of
NMR, types of this technique, and the advantages and disadvantages of NMR
spectroscopy. This article also provides an insight into the ongoing developments in the
field of NMR spectroscopy for future applications.
Keywords: Nuclear magnetic resonance; computer assisted tomography; multiple
sclerosis; electromagnetic radiation; metabolism; vibrational energy.
1. Introduction
X-rays have been routinely used in the field of medicine and dentistry to detect
abnormalities, fractures, and to observe healing tissues but this worthy detection tool
comes with a risk of exposing the patients to excessive radiations. Although x-rays are
swift and painless, still, long term exposure to their radiations could cause harmful effects
including cellular damage. Many new powerful analytical tools have been developed in the
recent years which are able to deliver precise results with minimal potential damage to the
body tissues.1
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NMR was first discovered in 1940’s.2 During the next few decades, it underwent
metamorphosis with new knowledge to create this device suited for various fields like
chemistry, medicine, and dentistry and resulted in grabbing six Nobel prize in the field of
spectroscopy
3
and the first application of NMR to study metabolism in a living tissue
dates back to 1970’s. In the present era, with ongoing improvements in magnetic and
equipment technologies, NMR spectroscopy and imaging can be utilized to explore an
extensive range of biological activities.
NMR spectroscopy makes full use of the magnetic properties of assured atomic nuclei and
is widely being used in the field of physics and chemistry. Most researchers utilize
NMR to determine the detailed molecular structures of solids, liquids, and gases as it gives
thorough information about the organization, motion, response state, and chemical
atmosphere of molecules.
4
In dentistry, this technique is predominantly beneficial to
explore the structure of amorphous glasses and dental cements. 5 It is also commonly used
to review the fluoridation of apatite surfaces in the tooth structure. 6
2. Basic mechanism of action of NMR
The basic principal of NMR is that the structural and chemical composition of different
substances can be determined by their nuclei, which have their distinctive magnetic field.
Every nuclei of a material is electrically charged and this property allows the nuclei to spin
due to its particular characteristic and quantum effect. The strength of the external
magnetic field causes electrically charged nucleus to move from a lower energy level (E1)
to a higher energy level (E2) and the difference between E2 and E1 is symbolized as ΔE
which is dependent on the power of the magnetic field and size of the nuclear field
moment. 7
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The NMR signal is attained by the electromagnetic radiation rhythm with a frequency
denoted by ‘v’ causing the nuclei to move to a higher energy level (E1 to E2). When this
electromagnetic radiation is stopped, it causes the nuclei to relax and accomplish thermal
equilibrium. This release of energy from the nuclei is recorded in the form of spectra on
the computer and this spectra is exclusive for every nuclei and is equivalent to the energy
levels between the two states (E2 and E1) (Fig. I) (Keeler, 2007).
2.1. Nuclear spin
The protons and neutrons of an atom exhibit spin. In some materials, the protons and
neutrons exhibit paired spin like carbon 12C, oxygen 16O and sulphur 32S and in these
cases, they cancel each other out thus, causing the nucleus not to spin. In some materials
the number of protons and neutrons in an atom are unpaired like in proton 1H, phosphorus
31P and fluoride 19 F. If the total of the protons and neutrons in an atom sums up to be an
odd number, than the nuclei will show half integer spin like 1/2, 3/2, 5/2. In cases where
number of neutrons and protons are both odd, the spin would be an integer spin like 1, 2,
3.8
2.2. Applied magnetic field and nuclear moment
The spin of the protons and neutrons creates a magnetic moment in the nucleus of an atom.
This magnetic moment could be towards the externally applied magnetic field or away
from it. This applied magnetic field is denoted by B0. The more desired direction of the
nuclear moment is towards the magnetic field which is at lower energy level denoted as α
compared to the path opposite to the magnetic field denoted as β5. The magnetic field is
accountable for retaining the distinction in the energy levels. If it does not happen, all the
orientations of the spin of 21+1 would be of equal energy.9
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2.3. Magnetic field strength
NMR requires a magnetic field that is both strong and uniform. The magnetic field
strength is measured in Tesla or MHz. NMR needs reference nuclei to represent the
strength of the magnetic field, which is mostly of high resonance frequency.
2.4. Chemical shift
Becker, 1999 proposed that whenever the outer magnetic field is applied, it has a
dissimilar result on the electrons as compared to its nucleus.
10
The movement of the
electrons creates a magnetic field in and around the nucleus. This magnetic field created is
different in direction as compared to the outer magnetic field. Any change in the magnetic
field causes a similar change in the spectrum of the NMR too. This sum of the shift is
controlled by nature of the nucleus and nature of the motion of electrons in its surrounding
atoms and molecules. This phenomenon is called “chemical shift” and a reference
compound is needed to measure the chemical shift.
11
Chemical shift make it possible to
determine and differentiate magnetically inequivalent nuclei present in a molecule.
2.5. Spin – spin coupling
The nuclei close to each other induce an incident called “spin – spin coupling” which
happens due to the difference in nuclei’s magnetic field direction. This direction could be
either towards or opposing the magnetic field, causing the splitting of NMR signals. This
magnetic field direction could either strengthen or fade the signals of NMR. The signals of
the NMR can split into two or more components depending upon the specific nuclei
having characteristic distance and relative potency. 12
2.6. Spin relaxation
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Spin relaxation is the comeback of energy levels to stability. This occurs due to the loss of
resonance signals with the passage of time after releasing the resonance frequency. There
are two relaxation processes allowing nuclear spin to return to stability. These are spin –
lattice relaxation and spin - spin relaxation. 13
Spin lattice relaxation, also called Longitudinal magnetic relaxation happens due to loss of
energy of the excited nuclei to the surrounding molecules which cause a change of spin
among their energy levels. The energy conveyed to the molecular frame is typically in the
way of transitional or vibrational energy.T1 represents the time for a specific nucleus to
come back to its thermal stability. A number of the elements such as structure, molecular
mass, temperature, and solution could influence this procedure. 14
Spin – spin relaxation, also called transverse relaxation happens when energy lost from the
nuclei cause loss of signals and the energy lost is conveyed to some other nearby spin
active nuclei. Spin – spin relaxation time (T2) is the half-life of this procedure.
3. Types of NMR spectroscopy
Solid state NMR is used for chemical analysis in order to recognize any changes in the
structure during phase transitions and different transformations in a solid state. The main
technique frequently used in a solid state NMR is magic angle spinning (MAS).
Magic angle is described as the angle which the sample makes with the direction of
magnetic field when it is lowered down into the vertical tube of the probe used in the
NMR. When the sample moves down in the tube, the neighboring magnet tilts to an angle
of 54.74, which is called the magic angle. This magic angle makes the resolution of the
sample more precise by making the broader lines of the NMR narrower. 15 At this angle the
nuclear bipolar interactions among the magnetic moments of nuclei averages to zero. This
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results in the signals to become narrower giving isotropic values and spinning side bands
which can be used to identify the chemical shift of the nuclei for structural determination
of solid materials.
3.1. Phosphorus NMR
In the solid state NMR, phosphorus is one of the isotopes used to study the molecules and
structures of different samples. This valuable tool has a medium sensitive nucleus that
gives sharp lines and has a wide chemical shift range.31P NMR has an influential approach
which has been used in various studies including natural ecosystems, forests, agriculture,
fertilizers and marine sediments. As 31P is the only naturally occurring phosphorus isotope,
all phosphorus species present in a certain sample can be detected by this NMR. 16The area
under each peak in NMR experiments should be proportional to the number of the
particular type of phosphorus nucleus, allowing the NMR to identify the different
phosphorus forms present in the sample. Compound classes of phosphorus which could be
identified in this NMR include ortho-phosphate di esters, pyrophosphate, polyphosphate,
phosphonates, ortho-phosphate monoesters, and ortho phosphates. 17
3.2. Proton NMR
Proton is the initial and the most frequent atom to be used in NMR spectroscopy. It is also
called 1H or hydrogen-NMR. With this technique, researchers are now capable to
investigate the complete composition of an organic material. 1H NMR spectra gives
information about the different varieties of hydrogen present in the molecule and also
gives information about its adjacent surroundings.18 1H NMR spectrum of main materials
shows small chemical shift range for usual compound being studied. This chemical shift
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ranges from +14 to -14ppm. It also has a broad difference in the extent of coupling
constant. 19
3.3. 29 Si MAS NMR
Silicon is an essential element and its
29
Si isotope, which is used in
29
Si NMR has4.70%
natural occurrence with ½ spin nucleus. It is another spectroscopic technique used to
investigate the structures of organic compounds. Its value of magnetic moment is a little
low causing a low resonance frequency. The predominance of
29
Si NMR shifts is present
in a range from +50 to 200 ppm. 20
3.4. 19F MAS-NMR
Isotopes of fluoride are naturally present in very less quantities except for the
19
F isotope.
Fluorine-19 is the only constant isotope of fluorine found in large quantities. Due to its
good nuclear qualities and a great quantity, it is used in
19
F MAS NMR technique.19F
NMR technique is very rapid when compared to 1H NMR technique and without a doubt,
19
F nucleus is one of the most amenable NMR nucleus. Fluorine has a spin of ½ nucleus.
Its nucleus in molecules is usually encircled by 9 electrons and its binding energy is
147801 keV. The sensitivity of
19
F NMR spectroscopy to its chemical shifts (in order to
study the fine details of the local surrounding) are much high for fluorinethus, making it
very reactive to NMR measurements with an extremely broad chemical shift range.
21 19
F
NMR spectroscopy selectively identifies the surroundings of just the fluorine atoms in the
study samples, allowing direct detection of the probable structural ranges in which fluorine
may be present within the sample in all forms. Most frequently 19F NMR spectroscopy is
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utilized to study the structure of fluorine containing materials. Interaction of fluoride with
hydroxyapatite forming fluorapatite can be studied with this technique.Yesinowski and
Mobley, 1983 verified the capacity of this NMR to differentiate between fluorapatite,
fluorohydroxyapitite, and calcium fluoride in massive phase and also on hydroxyapatite
surfaces.
0.1%.
22 19
23 19
F NMR can identify fluoride even in very small concentrations starting from
F NMR technique has also been used to study the metabolism of drugs
containing fluoride in them. 24
3.5. 13C NMR spectroscopy
This technique is a significant tool to recognize carbon atoms in any organic material. It
also gives detailed information regarding the chemical structure of the organic compound
being studied. 13C is an isotope of carbon which has a spin quantum number of 1/2 and is
only 1.1% naturally present and this isotope can be detected by 13C NMR.13C NMR is less
responsive to carbon in view of the fact that the main isotope of carbon is 12C, which is not
magnetically active therefore, it cannot be detected through this technique. The intensities
of the signals in carbon NMR are not usually comparative to the number of
corresponding 13Catoms. They are strongly reliant on the numerals of adjacent spins.
25
Magnets utilized in C NMR have a usual diameter of 10mm and its usual range of
chemical shift is much larger compared to proton NMR.13 C NMR can be used to find out
the composition of different molecules and is also used in the drug industry to verify drug
purity.
3.6. 27 Al MAS NMR
27
Aluminum MAS-NMR has a natural abundance of 100% and it has a 5/2 nuclear spin.
The nucleus of aluminum is very responsive giving wide lines over the broad range of
chemical shift. The main application of this NMR is to identify the existence of aluminum
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and to observe the probable structural changes of the different varieties of aluminum.
Therefore, it is a very useful tool to identify the structure of amorphous dental materials. In
a previous study performed on glass carbomerionomer cement, 27Al NMR has been used to
observe alteration of Al (IV) into Al (VI) in the setting glass carbomer cement. 26
4. Advantages of NMR spectroscopy
4.1. Non-invasiveness
The fundamental quality of nuclear magnetic resonance is its non-invasiveness. Due to
NMR the studies of biological cells and tissues is now possible without damaging the
sample. The fact that both spectrum and imaging can be obtained without destroying the
sample, is noticeably the greatest advantage of NMR in vivo studies. 27
4.2. Lack of ionizing radiation
Another major advantage of NMR is its lack of ionizing radiation. There are many
techniques being used in vivo studies involving ionizing radiations. NMR has made it
possible to avoid the exposure from radiation, which could be harmful for both the
researcher and the subject. NMR has the capability to utilize isotopes which are stable such
as carbon – 13 to measure metabolic fluxes instead of radioactive compounds. Moseley in
1982 observed that NMR not only minimizes the exposure to observer and subject from
the harmful rays but also eliminates the need to dispose of the radioactive tissues and other
materials that might be contaminated during the study. 28 Thus the application of NMR can
ensure the safety of the employees as well as reduces experimental cost due to the removal
of discarded radioactive substances.
4.3. Adjustability
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Extensive variety of processes can be investigated through NMR due to the flexibility of
the particular technique that can be applied. This technique not only gives information
about the physiology of the tissues but it also gives great images of those tissues. With
NMR, a single study can be performed with the same basic technique in both humans and
animals, which is important to increase the translation of information. The computed
tomography (CT) scan technique can only provide the imaging but not the metabolic or
anatomic details.
29
Whereas, NMR spectroscopy has the capability of acquiring a wide
variety of information.
4.4. Detailed structural analysis
Over the period of time, NMR has played a major responsibility in determining the
mechanisms and chemical connections at a molecular level. This technique has helped to
obtain information regarding the minute details about the physical and chemical
characteristics of structures. 30 NMR can also analyze the parameters of chemical shift and
it can give details on the local bonding environment around a particular atom, which could
be calculated for extended period of times with NMR
31
. It utilizes the pseudo wave
function to get information about large compoundstructures. 32 NMR has the capability to
assist studies of biochemical processes conducted in vivo, which is not efficiently achieved
with other imaging techniques. Lee et al., 1995 proposed that NMR is a better-quality
technique as compared to X-ray diffraction (XRD) in determining archaeological bone
structure.
33
In food industry, NMR has been utilized to observe the features of various
food products. 34
4.5. As a diagnostic tool
CT scan images of cranium are restricted by artifacts but this limitation does not occur
with NMR. In the field of medicine, NMR gives the benefit of identifying pediatric tumors,
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hematomas, and other pathologies.
35
Since multiple sclerosis is a very tricky disease to
identify, NMR has become the prime diagnostic device for multiple sclerosis. 36 NMR has
a particular use for certain body areas like brain where it produces very detailed and
definite images showing delineation between grey and white matter.
37
whereas, some
tissues such as bone, having low water percentage cannot emit strong signals to create
images for NMR.
38
Also, NMR is apparently victorious in identifying breast cancer at an
early stage. According to a radiologist at Cleveland, a mammogram cannot differentiate
between a small cancer and a spot, when there are multiple cysts in the breast but with
NMR, this distinction is possible.
39
NMR technique also gives good images of fatty
tissues and large quantity of fat creates very fine images. Therefore, researches on bone
marrow shows much potential. Also, diagnosis of vascular diseases is promising with the
NMR
40
as it enables the detailed structural analysis of the surfaces of blood vessels and
their abnormalities
5. Disadvantages of NMR spectroscopy
Although NMR technique has numerous advantages, few disadvantages are also present.
5.1. Presence of high magnetic field surroundings is essential
An unavoidable outcome when performing the NMR technique is the requirement to
perform in a surrounding which has a high magnetic field. The presence of the magnetic
field can affect the proper functioning of monitors and computer controlled devices. If any
sharp object like scalpel, scissor, or stapler is present in the NMR magnetic field area, it
can get attracted to the magnet field which can cause severe injuries to the workers.
Nowadays, monitoring devices being used in the magnetic field area are being designed to
function properly under the magnetic field. 41 Also instruments being used in NMR studies
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are made non-ferromagnetic to reduce the problems encountered with high magnetic field
surroundings. 42
5.2. Cost of performing NMR
NMR system cannot be purchased by a single investigator or for a single research because
of its high cost. Expenses increase further with the size of the NMR magnet and
maintenance costs of NMR are also high. 43 As a result, majority of the NMR systems are
often purchased by a group of researchers through programs which are approved by
research centers and also by funding grants. 44
6. Future directions
Further improvements to make more efficient NMR magnets should continue as it is
immensely upgrading the knowledge about the wide variety of different biophysical
processes. Advancements in the NMR technology, particularly in the imaging technique
and machinery design are needed to totally utilize its qualities and to make this research
technique more effective and accurate. Additional work should be performed to gain
information about the functional details of NMR as it would help to demonstrate more
extensive details of structures, functions, and metabolism of any material being
investigated.
The utilization of this valuable technique is limited because of its cost and availability. In
future, research centers and other medical programs should make its availability easy for
the researchers so that they can gain full benefits of NMR in their studies. It is now
essential for hospital management to do preparations for the modification of NMR services
and employment. Growth in the clinical area must go together with the proper expansion in
the management area, to make full use of this facility.
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7. Conclusion
Considering the potential advantages of the NMR technique, it can be concluded with
authority that it has become a preferred choice of technique for many procedures. NMR is
still a growing technology and it is being anticipated that few new discoveries are now just
around the corner.
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Figure captions
Fig. I: Showing a line in the spectrum is related with a transition between two energy
levels (E2 and E1) (Keeler, 2007).
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