Organic Chemistry Laboratory

Organic Chemistry Laboratory
Building A Toolset For The Identification of Organic Compounds Physical Properties Melting Point Boiling Point Density Solubility Refractive Index Chemical Tests Hydrocarbons Alkanes Alkenes Alkynes Halides Alcohols Aldehydes Ketones Spectroscopy Mass (Molecular Weight) Ultraviolet (Conjugation, Carbonyl) Infrared Functional Groups NMR (Number, Type, Location of protons) Gas Chromatography (Identity, Mole %) 4/19/2017

Spectroscopy The Absorption of Electromagnetic Radiation and the use of the Resulting Absorption Spectra to Study the Structure of Organic Molecules 4/19/2017

Spectroscopy Spectroscopy Types:
Mass Spectrometry (MS) – Hi-Energy Electron-Beam Bombardment Use – Molecular Weight, Presence of Nitrogen, Halogens Ultraviolet Spectroscopy (UV) – Electronic Energy States Use – Conjugated Molecules; Carbonyl Group, Nitro Group Infrared Spectroscopy (IR) – Vibrational & Rotational Movements Use – Functional Groups; Compound Structure Nuclear Magnetic Resonance (NMR) – Magnetic Properties of Nuclei Use – The number, type, and relative position of protons (Hydrogen nuclei) and Carbon-13 nuclei 4/19/2017

The Electromagnetic Spectrum
High Frequency () Low High Energy (E) Low Short Wavelength () Long Frequency 1.2 x 1014 Hz 3 x 108 Hz 3 x 1019 Hz 3 x 1016 Hz 1.5 x 1015 Hz 2 x 1013 Hz 3 x 1011 Hz 1 x 109 Hz 6 x 107 Hz 4 x103cm-1 1.25 x104cm-1 Wave Number 2.5 x104cm-1 0.002 cm-1 1 x109cm-1 1 x107cm-1 5 x104cm-1 667cm-1 10 cm-1 3 cm-1 0.01 cm-1 Cosmic &  Ray Vacuum UV X-Ray Infrared Microwave Radio Frequency 0.01 nm 10 nm 1 mm 30 cm 1 m 5 m Wavelength 200 nm 400 nm 800 nm 2.5  15  Near Ultraviolet Visible Vibrational Infrared Nuclear Magnetic Resonance Blue Red 4/19/2017

Nuclear Magnetic Resonance Spectroscopy
NMR Nuclear Magnetic Resonance Spectroscopy NMR 4/19/2017

NMR Nuclear Magnetic Resonance Spectroscopy (NMR) Nuclear Spin
Nuclear Spin State Magnetic Moments Quantized Absorption of Radio Waves Resonance Chemical Shift Chemical Equivalence Integrals (Signal Areas) Chemical Shift - Electronegativity Effects Chemical Shift - Anisotropy (non-uniform) effects of pi bonds Spin-Spin Splitting 4/19/2017

NMR NMR NMR is an instrumental technique to determine the number, type, and relative positions of certain Nuclei in a molecule NMR is concerned with the magnetic properties of these nuclei Many Nuclei types can be studied by NMR, but the two most common nuclei that we will focus on are Protons (1H1) and Carbon-13 (13C6) The magnetic properties of NMR suitable nuclei include: Nuclear Magnetic Moments Spin Quantum Number (I) Nuclear Spin States Externally Applied Magnetic Field Frequency of Angular Precession Absorption of Radio Wave Radiation - Resonance 4/19/2017

NMR The Magnetic Properties
Many atomic nuclei have a property called “Spin” Since all nuclei have a charge (from the protons in the nucleus), a spinning nuclei behaves as if it were a tiny magnet, generating its own Magnetic field The Magnetic Field of such nuclei has the following properties – Magnetic Dipole, Magnetic Moment and Quantized Spin Angular Momentum The Magnetic Moment (μ) of a nuclei is a function of its Charge and Spin and is defined as the product of the pole strength and the distance between the poles Only Nuclei with Mass & Atomic number combinations of Odd/Odd, Odd/Even, Even/Odd possess “Spin Properties,” which are applicable to NMR Note: Nuclei with a Mass & Atomic number combination of Even/Even do not have “Spin” and are not useful for NMR 4/19/2017

NMR Nuclear Spin States
Nuclei with spin (Magnetic Moment, Quantized Spin Angular Momentum, Magnetic Dipole) have a certain number of “Spin States.” The number of “Spin States” a nuclei can have is determined by its “Spin Quantum Number I,” a physical constant, which is an intrinsic (inherent) property of a spinning charged particle. The Spin Quantum Number (I) is a non-negative integer or half-integer (0, 1/2, 1, 3/2, 2, etc.). The Spin Quantum Number value for a given nuclei is associated with the Mass Number and Atomic Number of the nuclei. Odd Mass / Odd Atomic No - 1/2, 3/2, 5/2 Spin Odd Mass / Even Atomic No - 1/2, 3/2, 5/2 Spin Even Mass / Even Atomic No - Zero (0) Spin Even Mass / Odd Atomic No - Integral (1, 2, 3) Spin 4/19/2017

NMR Nuclear Spin States (Con’t)
The number of allowed Spin States for a nuclei is: I with integral differences ranging from +I to -I Ex. For I = 5/ I + 1 = 2 * 5/ = = 6 Thus, Spin State Values = 5/2, 3/2, 1/2, -1/2, -3/2, -5/2 The Spin Quantum number (I) for either a Proton (1H1) or a Carbon-13 (13C6) nuclei is 1/2 Thus, the number of Spin States allowed for either a Proton (1H1) or a Carbon-13 (13C6) nuclei is: [2 * ½ + 1 = = 2] Therefore, the two spins states for either nuclei are: + 1/2 & - 1/2 4/19/2017

NMR Nuclear Spin States (Con’t)
In the absence of an applied Magnetic field, all the spin states ( + ½ & - ½ ) of a given nuclei are of equivalent energy (degenerate), equally populated, and the spin vectors are randomly oriented When an external Magnetic Field is applied, the degenerate spin states are split into two opposing states of unequal energy + 1/2 spin state of the nuclei is aligned with the applied magnetic field and is in a lower energy state - 1/2 spine state of the nuclei is opposed to the applied magnetic field and is in a higher energy state There is a slight majority of the lower energy (+1/2) nuclei 4/19/2017

NMR Two Allowed Spin States for a Proton
Direction of an Externally Applied Magnetic Field (Ho) Ho Spin +1/2 Aligned Spin -1/2 Opposed - 1/2 Opposed to Field +1/2 Aligned E E + 1/2 Aligned with Field Ho -1/2 Opposed No Field Externally Applied Magnetic Field Ho Alignments Eabsorbed = (E-1/2 state E+1/2 state) = h E = f(Ho) The stronger the applied magnetic field (Ho), the greater the energy difference between the spin states 4/19/2017

NMR Applied Magnetic Field, Frequency of Angular Precession
Under the influence of an externally applied magnetic field, Nuclei with “Spin Properties,” such as Protons & Carbon-13, begin to Precess about the axis of spin with Angular Frequency ω, similar to a toy top The Frequency which a proton precesses is directly proportional to the strength of the applied magnetic field For a proton in a magnetic field of 14,100 gauss (1.41 Tesla), the Frequency of Precession is approximately 60 MHz That same proton, in a magnetic field of 23,500 gauss ( Tesla), will have a Frequency of Precession of approximately MHz The stronger the applied magnetic field, the higher the Frequency of Precession and the greater energy difference between the +1/2 and -1/2 spin states 4/19/2017

NMR NMR Spectrometers NMR spectrometers are rated according to the frequency, in MHz, at which a proton precesses - 60 MHz, 100 MHz, MHz, 600 MHz, or even higher. Continuous Wave (CW) NMR instruments are set up so that the externally applied magnetic field strength is held constant while a RF oscillator subjects the sample to the full range of Radio Wave frequencies at which protons (or C-13 nuclei) resonate. In Fourier Transform (FT) NMR instruments, the RF oscillator frequency is held constant and the externally applied magnetic field strength is changed. Most NMR instruments today are of the Continuous Wave type 4/19/2017

NMR Typically, Continuous Wave (CV) Spectrometers are used in which the externally applied magnetic field is held constant and RF Radio Oscillator applies a full range of frequencies at which protons or C-13 nuclei resonate 4/19/2017

NMR Energy Absorption, Resonance
If long wave radio radiation (1-5 m) is applied from a RF Oscillator to a sample under the influence of a strong externally applied magnetic field, and the frequency of the oscillating electric field component of the incoming radiation matches the Angular Frequency of Precession of the nuclei, the two fields couple and energy is transferred from the incoming radiation to the protons This causes the nuclei with +1/2 spin state to absorb energy and change to the -1/2 spin state When Energy is absorbed at specific frequencies it is referred to as being “Quantized” When a proton absorbs a radio wave, whose frequency matches its Angular Frequency of Precession, it is said to be in “Resonance” with the incoming signal 4/19/2017

NMR Electron Density, Frequency of Angular Precession
Protons exist in a variety of chemical and magnetic environments, each represented by a unique electron density configuration Under the influence of a strong externally applied magnetic field, the electrons around the proton are induced to circulate, generating a secondary magnetic field (local diamagnetic current), which acts in opposition (diamagnetically) to the applied magnetic field This secondary field shields the proton (diamagnetic shielding or diamagnetic anisotropy) from the influence of the applied magnetic field Recall from slide # 13 that the Angular Frequency of Precession is directly proportional to the applied Magnetic Field strength 4/19/2017

NMR Electron Density, Frequency of Angular Precession (Con’t)
As the shielding of the proton increases (increased electron density) it diminishes the net applied magnetic field strength reaching the proton; thus the Angular Frequency of Precession is lower If the electron density decreases, more of the applied magnetic field strength impacts the proton and it will precess at a higher Angular Frequency Thus, each proton with a unique electron density configuration will “Resonate” at a unique “Frequency of Angular Precession In a 60 MHz NMR Spectrometer all protons will resonate at a magnetic field strength of approximately 60 MHz, but each unique proton will resonate at its own unique frequency, with differences among unique protons of only tens of Hertz in a field of 60 MHz 4/19/2017

NMR NMR Spectra – Fourier Transform vs. Continuous Wave
In a Fourier Transform (FT) NMR, the spectrum produced is a plot of the magnetic field strength – representing the frequency of the resonance signal – on the X-axis – versus the intensity of the absorption on the Y-Axis. Each signal – consisting of one or more peaks – represents the “Resonance Frequency” of a particular type of proton with a unique chemical & magnetic (electron density) environment. 4/19/2017

NMR NMR Spectra – Fourier Transform vs. Continuous Wave
Fourier Transform (Con’t) As the pen of the recorder moves from left to right, the value recorded on X-axis of the NMR spectrum represents small increments of increasing magnetic field strength. The right side of the NMR Spectrum is referred to as being “Upfield” (higher magnetic field strength). The left side of the NMR Spectrum is referred to as being “Downfield” (lower magnetic field strength). 4/19/2017

NMR NMR Spectra – Fourier Transform vs. Continuous Wave (Con’t)
In a Continuous Wave NMR, the spectrum produced is a plot of the RF Radio Oscillator Frequency versus the intensity of the absorption on the Y-Axis. As before, each signal – consisting of one or more peaks – represents the “Resonance Frequency” of a particular type of proton with a unique chemical & magnetic (electron density) environment. As the pen of the recorder moves from left to right, the value recorded on X-axis of the NMR spectrum represents a decreasing RF Oscillator Frequency (Resonance Frequency) 4/19/2017

NMR NMR Spectra – Fourier Transform vs. Continuous Wave (Con’t)
The Signals on the right side of the NMR Spectrum represent protons (C-13 nuclei) that Resonate at lower frequencies. The Signals on the left side of the NMR Spectrum represent protons (C-13 nuclei) that Resonate at higher frequencies. 4/19/2017

NMR NMR Spectra – FT or CW: the spectrum looks the same
A FT or CW spectrometer will produce the same spectrum. The peaks on the right side of the spectrum represent those protons (or C-13 nuclei) that resonate at the highest externally applied magnetic field strength and the lowest frequency This statement would appear to be in conflict with the statement on Slide #13: “The Frequency which a proton Precesses is directly proportional to the strength of the applied magnetic field” This apparent conflict is resolved by consideration of the influence of the secondary magnetic field set up by the Diamagnetic Current from circulating valence electrons. This magnetic field opposes the externally applied field reducing the effect of the applied Magnetic Field on the proton, which in turn lowers the Resonance Frequency 4/19/2017

NMR NMR Spectra – FT or CW: the spectrum looks the same (Con’t)
The protons that resonate and produce signals on the right side of the NMR Spectrum (up field) have higher electron density shields than protons that resonate downfield The net effect of the difference between the externally applied magnetic field and the amount prevented from actually reaching the proton results in a significantly reduced Resonance Frequency As the NMR spectrum moves from right to left, the electron density about the various proton environments is decreasing, resulting in more of the externally applied magnetic field getting through to the proton As this net magnetic force is increasing downfield toward the left side of the spectrum, the Resonance Frequency increases in conformance with the statement on Slide #13 4/19/2017

NMR NMR Spectra – Background Summary Absorption Signal
TMS PPM 13 In a continuous Wave NMR, the strength of the externally applied magnetic field is held “constant”. Protons that produce signals on the right side of the NMR spectrum have a higher amount of valence electron shielding. The Magnetic Field produced by circulating valence electrons (Diamagnetic Current) opposes the externally applied Magnetic Field. The Diamagnetic Field diminishes the amount of Applied Magnetic Field reaching the proton. The net amount of magnetic force impacting the proton is reduced resulting in a lower Resonance Frequency. As the Electron Density about a proton decreases downfield, the Resonance Frequency increases because more of the applied Magnetic Field impacts the Proton. Applied Magnetic Field Strength – Ho is held constant Applied Radio Frequency - RF Shielding of Proton by Valence Electrons Diamagnetic (Anisotropic) Magnetic Field Strength Produced by Circulation of Valence Electrons Net Magnetic Field Impacting Proton Frequency of Angular Precession (Resonance Frequency) 4/19/2017

NMR NMR Spectra – The Chemical Shift
The differences in the applied Magnetic Field strength (Angular Frequency of Precession) at which the various proton configurations in a molecule Resonate are extremely small The differences amount to only a few Hz (parts per million) in a magnetic field strength of 60, 100, 300, MHz (megahertz) It is difficult to make direct precise measurements of resonance signals in the parts per million range 4/19/2017

NMR NMR Spectra – The Chemical Shift
The typical technique is to measure the difference between the Resonance signals of various sample nuclei and the Resonance signal of a standard reference sample (see slides 25 & 26) A parameter, called the “Chemical Shift” (), is computed from the observed frequency shift difference (in Hz) of the sample and the “standard resonance signal” divided by the applied Magnetic Field rating of the NMR Spectrometer (in MHz) Thus, the Chemical Shift () is field-independent of the Magnetic Field rating of the instrument 4/19/2017

“Parts Per Million” (ppm)
NMR NMR Spectra – The Chemical Shift (Con’t) The Chemical Shift is reported in units of: “Parts Per Million” (ppm) Ex: If a proton resonance was shifted downfield 100 Hz relative to the standard in a 60 MHz machine, the chemical shift would be:  = 100 Hz / 60 MHz = 1.7 ppm By convention, the Proton Chemical Shift values increase from right to left, with a range of 0 – 13 In other words: Chemical Shift values decrease with increasing Magnetic field strength or Chemical Shift values increase with increasing Resonance frequency! 4/19/2017

NMR NMR Spectra – The Internal Reference Standard
The universally accepted standard used in NMR is: Tetramethylsilane (TMS) The 12 protons on the four carbon atoms have the same chemical and magnetic environment and they resonate at the same field strength, i.e., one signal (1 peak) is produced The protons are highly protected from the applied magnetic field because of high valence electron density The strength of the Diamagnetic Field generated by the valence electrons in TMS is greater than most other organic compounds 4/19/2017

Thus, little of the applied magnetic field gets through to the TMS protons reducing the Frequency of Angular Precession (Resonance Frequency) to a value that is lower than most other organic compounds. For most all other Proton environments, the electron density is less than TMS and slightly more of the applied magnetic field gets through to the protons resulting in a slightly higher frequencies of Angular Precession. 4/19/2017

The TMS signal appears on the far right hand side of the X-axis. Small amount TMS in the sample produces large signal By definition, the Chemical Shift value for TMS is “0 ppm” Thus, most all other protons will have Chemical Shifts > 0 and will be downfield from the TMS signal. 4/19/2017

NMR NMR Spectra – Simple Example Absorption Ethane
All six protons of Ethane are chemically and magnetically equivalent and all resonate at the same frequency producing one signal consisting of “one” peak, i.e., a singlet. An NMR Signal can consist of one or more “peaks” Multiple peaks are produced by a phenomenon called “spin-spin splitting” Note – See slides for a discussion of Spin/Spin Splitting For the chemically equivalent protons in Ethane there is no splitting, thus the signal consists of “one” peak, a singlet See next slide for more NMR Spectrum examples, showing basic splitting patterns (6) Signal (singlet) Absorption Ethane TMS Chemical Shift  (PPM) Typical location (1 ppm) of resonance signal for Methyl group protons not under the influence of an electronegative group (see slide ) Note the “6” at the top of the signal This is the peak integration value and represents the electronically integrated area under the signal curve and is proportional to the number of Protons generating the signal, i.e., Ethane has 6 chemically and magnetically equivalent protons See slides for a discussion of signal integration 4/19/2017

Therefore, the signal is a singlet with no splitting.
NMR NMR – Simple Examples The Six (6) equivalent Methyl Protons are represented as a Triplet at about 1 ppm. The 3 Triplet peaks are produced by Spin-Spin splitting based on the 2 protons attached to the Methylene Group (n + 1 rule). Chemical Shift  (PPM) Propane The Two (2) equivalent Methylene Protons are represented as a Septet at about 2 ppm. The 7 Septet peaks are produced by spin-spin splitting based on the 6 protons attached to the two Methyl groups (6 +1 = 7). (6) (2) TMS (3) (5) 5 unsubstituted Protons on Benzene ring are not equivalent, producing complex spitting patterns typical of the resonance structures in aromatic rings. See slides The Methyl group donates electrons to Benzene ring activating it. The Methyl protons have less electron density (deshielded), thus, the Chemical Shift is moved downfield. 3 equivalent Protons on Methyl Group Carbon attached to a Benzene ring Carbon that has no attached protons. Therefore, the signal is a singlet with no splitting. Toluene 4/19/2017

NMR Chemical Equivalence
Protons in a molecule that are in chemically identical environments will often show the same chemical shift Protons with the same chemical shift are chemically equivalent Chemical equivalence can be evaluated through symmetry Protons in different chemical environments have different chemical shifts, i.e. a signal is produced for each. Chemicals giving rise to 1 NMR signal Chemicals giving rise to 2 NMR signals H CH3 H H H H O CH3 C O CH3 H H H H H CH3 Benzene Cyclopentane Methyl Acetate 1,4 dimethyl benzene (p-xylene) CH CH3 C O CH3 O CH2Cl Acetone 1-Chloro Methyl Ether 4/19/2017

NMR An Isomer Example – C5H12O CH3 C CH2OH CH3 2-Dimethyl Propanol
tms a 9 c 1 b 2 CH3 C CH2OH CH3 (a) (b) (c) Signals  Rel Area Value of Signal a ~ b > c ~ 2-Dimethyl Propanol 9 protons on 3 Methyl groups are equivalent and are not under the influence of the electronegative OH group. 2 protons on Methylene group are equivalent and are influenced by electronegative OH group. The proton on OH group is concentration and hydrogen bonding dependent. Location on spectrum variable. Note: All signals are “singlets”, i.e., no adjacent protons to produce spin-spine splitting. tms a 9 b 3 (a) CH3 CH3 C O CH3 (b) Signals  Rel Area Value of Signal a ~ b >> t-Butyl Methyl Ether 9 protons on 3 Methyl groups are equivalent and not under the influence of electronegative group. 3 protons on single Methyl groups are equivalent and are under influence of electronegative oxygen. 4/19/2017

NMR Integrals (Signal Area)
An NMR spectrum also provides means of determining How Many of each type of proton the molecule contains. The Area under each signal is proportional to the number of protons generating that signal. In the Phenylacetone example below there are three (3) chemically distinct types of protons: Aryl (7.2 ppm), Benzyl (3.6 ppm), Methyl (2.1 ppm) The three signals in the NMR spectrum would have Relative Areas in the ratio of 5:2:3. Thus, 5 Aryl protons, 2 Benzyl protons, and 3 Methyl protons Phenylacetone 7.2 ppm (5 protons) 2.1 ppm (3 protons) 3.6 ppm (2 protons) 4/19/2017

NMR NMR Spectrum – Phenylacetone (103-79-7) C9H10O Ring 5 Protons
Methyl 3 Protons Methylene 2 Protons C9H10O 4/19/2017

NMR Integrals (Signal Area) (Con’t)
NMR Spectrometer electronically integrates the area under a signal and then traces rising vertical lines over each peak by an amount proportional to the area under the signal – see next slide. The heights of vertical lines give RELATIVE numbers of each type of hydrogen. Integrals do not always correspond to the exact number of protons, e.g., integrals of 2:1 might be 2H:1H or 4H:2H or... Computation Draw Horizontal lines separating the adjacent signals. Measure vertical distance between the Horizontal lines. Divide each value by the smallest value. Multiple each value by an integer >1 to obtain whole numbers. See example computation on next Slide. 4/19/2017

NMR Integrals (Signal Area) (Con’t)
NMR Spectrum – Benzylacetate (C9H10O2) Peak 7.3 ppm (c) - (h1) Div Peak 5.1 ppm (b) - (h2) Div Peak 2.0 ppm (a) - (h3) Div h1 h2 h3 (a) (b) (c) 55.5 div 22.0 div = 2.52 22.0 div = 1.00 32.5 div 22.0 div = 1.48 2.52 : 1.00 : 1.48 5 : : 3 c : b : a Each value multiplied by “2” to obtain integral values 4/19/2017

NMR Chemical Shift – Impact of Electronic Density Valence Electrons
In the presence of the applied magnetic field, the valence electrons in the vicinity of the proton are induced to circulate (Local Diamagnetic Current) producing a small secondary magnetic field The greater the electron density circulating about the nuclei, the greater the induced magnetic shielding effect The induced magnetic field acts in opposition (diamagnetically opposed) to the applied magnetic field, thus shielding the proton from the effects of the applied field in a phenomenon called Local Diamagnetic Shielding or Diamagnetic Anisotropy As the Diamagnetic Anisotropy increases, the amount of the applied magnetic field reaching the proton is diminished, decreasing the frequency of Resonance 4/19/2017

NMR Chemical Shift - Anisotropy (non-uniformity)
For some proton types, the chemical shifts can be complicated by the type of bond present Aryl compounds (benzene rings), Alkenes (C=), Alkynes (C ), and Aldehydes (O=CH) show anomalous resonance effects caused by the presence of  electrons in these structures The movement of these electrons about the proton generate secondary non-uniform (anisotropic) magnetic fields The relative shielding and deshielding of protons in groups with  electrons is dependent on the orientation of the molecule with respect to the applied magnetic field 4/19/2017

NMR Chemical Shift - Anisotropy (non-uniformity) (Con’t)
The Diamagnetic Anisotropic effect diminishes with distance In most cases, the effect of the Diamagnetic Anisotropic effect is to Deshield the protons, increasing the Chemical Shift In some cases, such as acetylene hydrogens, the effect of the anisotropic field is to shield the hydrogens, decreasing the Chemical Shift In a Benzene ring , the  electrons are induced to circulate around the ring by the applied magnetic field, creating a ring current, which in turn produces a magnetic field further influencing the shielding of the ring protons 4/19/2017

NMR Chemical Shift - Anisotropy (non-uniformity) (Con’t)
The presence of ring current causes the applied magnetic field to become non-uniform (diamagnetic anisotropy) in the vicinity of the benzene ring The effect of the anisotropic field is to further deshield the benzene protons, increasing the chemical shift Thus, protons attached to the benzene ring are influenced by three (3) magnetic fields: Strong Applied Magnetic Field Local Diamagnetic Shielding by Valence Electrons Anisotropic Effect from the Ring Current The net effect of the deshielding of the Benzene Ring protons is to increase the Chemical Shift far downfield to about 7.0 ppm 4/19/2017

NMR Electron Density and Electronegativity
Protons in a molecule exist in many different electronic environments (Methyl group (CH3), Methylene group (CH2),  bonds, unsubstituted Benzene ring Protons, Amino protons (NH), Hydroxyl protons (OH), etc.) Each proton with a unique electron density configuration will have a unique Angular Frequency of Precession The electron density of a given proton and thus, the frequency of precession, can be further influenced by the presence of electronegative groups in the vicinity of the proton Electronegative groups (or elements) are electron withdrawing, pulling electron density away from the proton 4/19/2017

NMR Chemical Shift – Impact of Electronegative Elements
The decrease in electron density about the proton results in a lower secondary magnetic field, a diminished shielding effect, an increase in the strength of the applied magnetic field reaching the nuclei, resulting in an increase in the precession frequency Electronegative elements are electron withdrawing When added to a carbon atom with protons attached, the Electronegative element withdraws electron density about the proton Reducing electron density deshields the proton from the effect of the applied field, allowing more of the magnetic field to impact the proton 4/19/2017

NMR Chemical Shift – Impact of Electronegative Elements (Con’t)
Recall that Deshielding the proton increases the Resonance Frequency producing a greater chemical shift, i.e., the resonance peak is moved downfield to the left on the spectrum The chemical shift increases as the electronegativity of the attached element increases Multiple substitutions have a stronger effect than a single substitution Electronegativity also affects the Chemical Shift of Protons further down the chain. But the effect is diminished as distance from the Electronegative Element increases 4/19/2017

NMR Chemical Shift – Impact of Electronegative Elements
Compound CH3X CH3F CH3OH CH3Cl CH3Br CH3I CH4 (CH3)4Si Element X F O Cl Br I H Si Electronegativity of X Chemical Shift (ppm) 3.59 ppm 1.53 ppm CH CH3OH CH3CH2OH CH3CH2CH2OH 0.23 ppm 3.39 ppm 1.18 ppm 0.93 ppm 3.49 ppm Note: The Chemical Shift of the Proton increases as the distance from the Electronegative Oxygen increases. 4/19/2017

NMR Chemical Shift values of typical
Proton environments and the effects of Electronegative Elements on the Chemical Shift. -OH, -NH TMS  (ppm) CH2F CH2Cl CH2Br CH2I CH2O CH2NO3 CH2Ar CH2NR2 CH2S C C H CH2 C Methine (1H) C CH C C H C CH2 C Methylene (2H) CHCl3 C CH3 Methyl (3H) Acids RCOOH ppm Aldehydes RCOH Phenols ArOH Alcohols ROH Amines RNH Amides RCONH Enols CH=CH-OH 15.0 Groups with variable chemical shifts (Protons attached to elements other than Carbon) O CH2 Effects of Electronegativity F > O > Cl = N > Br > S > I Electronegative Elements will pull electron density away from the proton diminishing the electron density. Proton is exposed to increased effects of the applied magnetic field, which increases the frequency of absorbance (Chemical Shift) moving the Resonance Signal downfield to the left. 4/19/2017

-Disubstituted Aliphatic Aromatic & Heteroaromatic
NMR General Regions of Chemical Shifts Aliphatic Alicyclic (CH2, CH3) -Substituted Aliphatic Alkyne -Monosubstituted Aliphatic -Disubstituted Aliphatic Alkene Aromatic & Heteroaromatic Aldehydic Carboxylic TMS  (ppm) 4/19/2017

NMR Approximate Chemical Shifts Protons (1H1) Carbon (13C6)
Type of Proton Chemical Shift,  (ppm) Type of Carbon Atom Chemical Shift ,  (ppm) 1o Alkyl, RCH 2o Alkyl, RCH2R 3o Alkyl, R3CH Allylic, R2C C CH R Ketone, RCCH O Benzylic, ArCH2-R Acetylenic, RC CH Alkyl Iodide, RCH2I Ether, ROCH2R Alcohol, HOCH2R Alkyl Bromide, RCH2Br Alkyl Chloride, RCH2Cl Vinylic, RC2 CH Vinylic, RC2 CH2-R Aromatic, ArH Aldehyde, RCH Alcohol hydroxyl, ROH a Amino, R NH a Phenolic, ArOH a Carboxylic, RCOOH a 1o Alkyl, RCH 2o Alkyl, RCH2R 3o Alkyl, RCHR Alkyl Halide or Amine, C-X Alcohol or Ether, C-O Alkyne, C Alkene, C = Aryl, Ar Nitriles, -C N O Amides, -C - N Carboxylic Acids, Esters, C O Aldehydes, Ketones, -C C- a Chemical shifts of these protons vary in different solvents and with temperature 4/19/2017

NMR Functional Chemical Functional Chemical Group Shift, ppm Group Shift, ppm TMS (CH3)4Si 0 Aromatic AR – H 6.5 – 8.0 Cyclopropane AR – C –H (benzyl) 2.3 – 2.7 Alkanes Fluorides RCH F – C – H 4.2 – 4.8 R2CH2 1.3 Chlorides R3CH 1.5 Cl – C – H 3.1 – 4.1 Cl Alkenes Cl – C – H 5.8 C = C – H 4.6 – 5.9 C = C – CH3 1.5 – 2.5 Bromides Br – C – H 2.5 – 4.0 Alkynes C  C – H 1.7 – 2.7 Iodides C  C – CH3 1.6 – 2.6 I – C – H 2.0 – 4.0 Nitroalkanes O2N – C – H 4.2 – 4.6 4/19/2017

NMR Functional Chemical Functional Chemical Group Shift, ppm Group Shift, ppm Alcohols Carboxylic Acids H – C – O – H 3.4 – O R – O – H 0.5 – 5.0 H – O – C – C – H 2.1 – 2.6 Phenols O Ar – O – H 4.0 – 7.0 R – C – O – H 11.0 – 12.0 Amines R – NH2 0.5 – Ketones Ethers O R – O – C - H 3.2 – R – C – C – H 2.1 – 2.4 Acetals R – O R Aldehydes C O R – O H R – C – H 9.0 – 10.0 Esters Amides O O R – O – C – C – H 3.5 – R – C – N – H 5.0 – 9.0 4/19/2017

NMR Spin – Spin Splitting
In addition to the Chemical Shift and Signal Area, the NMR spectrum can provide information about the number of the protons attached to a Carbon atom. Through a process called “Spin-Spin Splitting, a Proton or a group of equivalent Protons can produce “multiple” peaks (multiplets). Protons on a Carbon atom are affected by the presence of Protons on nearby, generally adjacent atoms. Spin - Spin splitting is the result of the interaction or coupling of the +1/2 & -1/2 spins of the protons on the adjacent carbon atoms. Spin - Spin coupling effects are transferred primarily through the bonding electrons 4/19/2017

NMR Spin – Spin Splitting (Con’t)
Those Protons on the adjacent Protons aligned with the applied magnetic field (+1/2 spin state), will transfer Magnetic Moment to, and thus augment, the strength of the magnetic field applied to the Proton sensing the adjacent Protons. This increase in the magnetic field strength affecting the sensing Proton makes it more difficult for the “secondary” or “diamagnetic” field produced by the valence electrons to protect the proton; thus, the Proton is “deshielded” causing the Chemical Shift to increase slightly 4/19/2017

NMR Spin – Spin Splitting (Con’t)
If the spins of the adjacent Protons are opposed to the magnetic field (-1/2 spin state), the strength of the applied magnetic field around the sensing proton is slightly decreased With a reduced applied magnetic field strength, the secondary diamagnetic field is better able to “shield” the Proton from the applied field resulting in a slight decrease in the Chemical Shift (increased “Resonance Frequency”) With 2 or more Protons on the adjacent Carbon atoms, there will be mixtures of +1/2 & -1/2 spins states producing unique Chemical Shift effects 4/19/2017

NMR Each unique Proton or group of equivalent Protons “senses” the number of Protons on the Carbon atom(s) next to the one it is bonded, and splits its resonance signal into n+1 signals, where “n” is the number of Protons on the adjacent Carbon atom(s) The “n+1” value represents the number of unique combinations of the +1/2 and -1/2 spin states of the adjacent Protons 4/19/2017

NMR Spin-Spin Splitting (Con’t) 1,1,2-Trichloroethane
Tert-Butyl Methyl Ether (a) (a) (b) (a) All protons chemically equivalent (a) protons & (b) protons are separated by more than three (3)  bonds No signal splitting - 2 signals (a) & (b) b 3H a 9H Possible spin combinations of adjacent protons TMS +1/ /2 Net Spin Signal Intensity 4/19/2017

NMR Spin-Spin Splitting – An example 1,1,2-Trichloroethane 4/19/2017

NMR Spin - Spin Splitting - Multiplet Signal Intensities
Pascal’s Triangle (a) (b) No. Adjacent Protons No. Peaks Seen Example Spectrum: Ethyl group CH3 CH2 Relative Intensity (b) (a) Note Relative Signal Intensities Singlet Doublet Triplet Quartet Quintet Sextet Septet 1 3.20  1.83 = spin +1/2 = spin -1/2 Net Spin +3/2 +1/2 -1/2 -3/2 Intensity Intensity ratios derived from the n + 1 rule Each entry is the sum of the two entries above it to the left and right. The relative intensities of the outer signals in sextet & septet multiplets are very weak and sometimes obscured. There are 3 times as many protons with +1/2 or - 1/2 spin arrangements than +3/2 & -3/2 Therefore, the signal intensities are greater. 4/19/2017

NMR Spin - Spin Splitting - Common Splitting Patterns       
Singlet Doublet No. signals produced based on the no. of adjacent protons X CH CH Y (X  Y) 2 signals (see 1) 2 signal (see 1)   Triplet Quartet CH2 CH 2 signals (see 1) 3 signals (see 2)   3 signals (see 2) X CH2 CH2 Y (X  Y) 3 signals (see 2) Quintet Sextet 2 signals (see 1) CH3 C H 4 signals (see 3)   3 signals (see 2) CH3 CH2 4 signals (see 3) Septet CH3 CH 2 signals (see 1) 7 signals (see 6)  4/19/2017

NMR Spin - Spin Splitting - Isomer Example CH3 CH2 CH2 Cl (a) (b) (c)
1-Chloropropane 3 signals Signal Rel Chem Rel Signal Neighbors Multiplicity Shift Area a lowest (Triplet) b middle (Sextet) c highest (Triplet) a c b 0 ppm Cl CH3 CH CH3 (a) (b) 2-Chloropropane 2 signals a Signal Rel Chem Rel Signal Neighbors Multiplicity Shift Area a lowest (Doublet) b highest (Septet) b 0 ppm 4/19/2017

NMR Spin - Spin Splitting - Coupling Constant
The Coupling Constant (J) is the spacing between the component signals in a multiplet. The distance is measured on the same scale as the chemical shift (Hz or cycles per second (CPS)). Note: 60 Hz = 1 ppm in a 60 MHz instrument. The Coupling Constant has different magnitudes for different types of protons H H H a,a 8-14 Hz a,e Hz e,e Hz H H C C Ortho 6-10 Hz 6-8 Hz H H H 11-18 Hz H para 1-4 Hz cis Hz trans Hz H 6-15 Hz H H O H meta 0-2 Hz cis Hz trans 1-3 Hz 0-5 Hz H H CH H H 4-10 Hz 8-10 Hz 5-7 Hz 4/19/2017 H C C CH 0-3 Hz

NMR Magnetic Equivalence
In the spin-spin example of 1,1,2-Trichloroethane, the two (geminal) protons attached to the same carbon atom (HB & HC), do not split each other H H Cl C C Cl Cl H A B C H H Cl C C Cl Cl H A B C They behave as an integral group. Protons attached to the same carbon atom and have the same chemical shift do not show spin-spin splitting. These protons are coupled to the same extent to all other protons in the molecule. They have the same Coupling Constant value J to the HA proton. Protons that have the same chemical shift and are coupled equivalently to all other protons are magnetically equivalent and do not show spin-spin splitting. 4/19/2017

NMR Differentiation of Chemical and Magnetic Equivalence
Br CH3 Br HA HB CH3 Cyclopropane Compound Two geminal protons (HA & HB) are chemically equivalent, but not magnetically equivalent Proton HA is on same side of ring as two halogens Proton HB is on same side of ring as the two methyls Protons HA & HB, therefore have different chemical shifts They couple to one another and show spin-spin splitting Two doublets will be seen for both HA & HB Coupling Constant J for them is about 5 Hz 4/19/2017

NMR Differentiation of Chemical and Magnetic Equivalence (Con’t)
HA HC C = C HB X Vinyl Compound Geminal protons (HA & HB) are chemically equivalent, but not magnetically equivalent Protons HA & HB have different chemical shifts Each has different coupling constant with HC Constant JAC is a cis coupling constant Constant JBC is a trans coupling constant Therefore, HA & HB are not magnetically equivalent They do not act as group to split proton HC HB splits HC with constant JBC into a doublet HA splits each component of doublet into doublets with coupling constant JAC 4/19/2017

NMR Proton (1H) NMR Spectrum and Splitting Analysis of Vinyl Acetate
Ha & Hb chemically equivalent, but not magnetically equivalent. Each has different chemical shift. Each has different coupling constant with Hc. Hb splits Hc into doublet (Jbc). Ha then splits each Jbc doublet into a doublet. Similary, Ha splits Hc into doublet (Jac). Hb then splits each Jac doublet into a doublet. Hc splits Ha & Hb into doublets. Ha & Hb each then split these doublets. 4/19/2017

NMR Aromatic Compounds (Substituted Benzene Rings)
We have previously stated that a magnetic field applied to an Aromatic ring becomes non-uniform (anisotropic) by the stabilizing effect of the Benzene Ring Current resulting in the protons being deshielded (electron density becomes less); thus, increasing the chemical shift. i.e., the absorption signal (Resonance Frequency) moves to the left on the chart – in the vicinity of 7.0 ppm. Depending on the number and type of groups substituted on an Aromatic ring, the NMR spectra of the remaining protons on the ring are often complex, with the Chemical Shift moving up field or downfield. 4/19/2017

NMR Some groups, such as – Cyano, Nitro, Carboxyl, Carbonyl – are electron-withdrawing (deactivate the ring), decreasing the electron density, and resulting in an increase in the Chemical Shift, i.e., resonance frequency moves further down field. For Electron-Withdrawing groups the Ortho & Para protons lose more electron density that the Meta protons; thus, are less shielded moving (increasing) the chemical shift downfield relative to the Meta protons. 4/19/2017

NMR Aromatic Compounds (Substituted Benzene Rings) (Con’t)
Electron-donating groups such as – Methyl, Methoxy, Amino, Hydroxy – activate the ring and increase the electron density resulting in a decrease in the Chemical Shift, i.e., resonance frequency moves up field to the right. For Electron–Donating groups, the Ortho & Para protons gain more electron density than the Meta protons; thus are more shielded moving (decreasing) the chemical shift up field slightly from the Meta protons. Mono – Substituted Aromatic Rings When a single substituted group is neither strongly electron- withdrawing (deactivates ring by decreasing electron density about the ring protons) nor strongly electron-donating (activates ring by increasing the electron density) – Methyl & Alkyl groups – , all ring protons (ortho, meta, para) have near identical chemical shifts resulting in a slightly broad singlet (the protons are not quite chemically equivalent). See pattern “A” on slide 73 4/19/2017

NMR Aromatic Compounds (Substituted Benzene Rings) (Con’t)
Mono – Substituted Aromatic Rings (Con’t) In general, electron withdrawing groups (Cyano, Nitro, Carboxyl, Carbonyl) decrease the electron density of the Ortho & Para protons more so than the Meta protons, resulting in the signal for the O & P protons being slightly more downfield than the Signal for the Meta protons as seen in pattern “C” on slide 73). In the case of electron withdrawing groups with double bonds such as Nitro (NO2) and Carbonyl (C=O) groups, or other double bonds attached directly to the ring, Magnetic Anisotropy causes the Ortho protons to be much more deshielded than the Para & Meta protons, resulting in the Ortho protons having a significantly increased Chemical shift as seen in pattern “D” on slide 73. In the case of electron donating group such as Methyl, Methoxy, Amino, Hydroxy, the Chemical Shift of the Ortho & Para protons, while not exactly the same, will be distinctly up field from the Meta protons as seen in pattern “B” on slide 73. 4/19/2017

NMR Aromatic Compounds (Substituted Benzene Rings) Con’t)
Mono – Substituted Aromatic Rings (Con’t) For Monosubstituted Electronegative elements, such as Halides, which are electron withdrawing due to the Dipole effect, the electron withdrawing effect is less dominant than the electron donating resonance effect. Thus, the increased electron density about the Ortho & Para protons would be increased relative to the Meta protons, resulting in an decrease in the Chemical Shift – signal moves up field as seen in pattern “E” on slide 64. Note: The “m/p” signal is actually an overlapping of the “m” and “p” signals with the “p” signal slightly up field from the “m” signal. The “o” proton has more electron density than the “p” proton because of the Magnetic Anisotropy effects of the ring current. 4/19/2017

NMR Aromatic Compounds (Substituted Benzene Rings) Con’t)
Para – Disubstituted Rings P-Disubstituted patterns are generally easy to recognize. When the Aromatic ring has two groups substituted in the para position, three distinct patterns are possible, depending on the relative electronegativity of the two groups. If the two p-substituted groups are identical, the four remaining protons on the ring are chemically and magnetically equivalent producing a singlet as seen in pattern “F (a)” on slide 73. If the two p-substituted groups are different, the protons on one side of the symmetrically ring split the protons on the other side of the ring into a doublet. The patterns produced by the two doublets will be different depending on the relative electronegativity of the two substituted groups as seen in patterns F (b) & F (c) on slide 73. 4/19/2017

NMR Common Aromatic Patterns 4/19/2017

NMR “Activating” and “Deactivating” groups and the impact of the changing electron density in the Benzene ring on Chemical Shift of ortho, meta, para protons Methoxyl (0-CH3) group is Electron Donating, activates ring by adding electron density to o/p protons. Chemical Shifts, , of ring o/p protons are moved up field, i.e., decreasing ppm because of increase electron density. Note location of “Methyl Protons” absorption at 3.7 ppm (without influence of “O” it would be around 1 ppm). m o, p m p o 3 Methyl Protons Anisole (C7H8O) 4/19/2017

NMR “Activating” and “Deactivating” groups and the impact of the changing electron density in the Benzene ring on Chemical Shift of ortho, meta, para protons m o/p The Amino group is Electron Donating and Activates the ring. Increases electron density around Ortho & Para protons relative to Meta. Chemical Shift, , of ring protons is up field, decreased ppm o m p 2 Amino Protons Aniline (C6H7N) 4/19/2017

NMR “Activating” and “Deactivating” groups and the impact of the changing electron density in the Benzene ring on Chemical Shift of ortho, meta, para protons o Nitro group is electron withdrawing and deactivates the ring. Protons in ring are deshielded moving Chemical Shift downfield. Magnetic Anisotropy causes the Ortho protons to be more deshielded than the Para & Meta protons. p m o m p Nitrobenzene (C6H5NO2) 4/19/2017

NMR “Activating” and “Deactivating” groups and the impact of the changing electron density in the Benzene ring on Chemical Shift of ortho, meta, para protons Ha Ha’ Hb Hb’ Ha&Ha’ Hb&Hb’ 2 Amino Protons The Molecular Ion peak from Mass Spectrometry would have indicated the presence of the single Chlorine atom and Nitrogen. Para Di-Substituted Benzene ring Ha & Ha’ have same Chemical Shift Hb & Hb’ have same Chemical Shift Ha is split into doublet by Hb Hb is split into doublet by Ha Two sets of peaks produced by relative electronegativity of Amino & Cl groups P-Chloroaniline (C6H6ClN) 4/19/2017

NMR “Activating” and “Deactivating” groups and the impact of the changing electron density in the Benzene ring on Chemical Shift of ortho, meta, para protons 2,4-Dinitroanisole (C7H6N2O5) c b a The Methoxy group is moderately activating, while the Nitro groups are strongly deactivating (electron withdrawing) Net effect is to Decrease the electron density about the ring protons The a & b protons are Ortho to the strongly deactivating Nitro groups, thus, they have reduced electron density and their Chemical Shift is down field relative to the “c” proton All protons interact to produce Spin-Spin Coupling. 3H 4/19/2017

NMR Protons attached to atoms other than carbon atoms
Widely variable ranges of absorptions. Protons on heteroelements, such as oxygen (hydroxyl, carboxyl, enols), and nitrogen (amines, amides) normally do not couple with protons on adjacent carbon atoms to give spin- spin splitting. Solvent effect - The absorption position is variable because these groups undergo varying degrees of hydrogen bonding in solutions of different concentrations. Amount of hydrogen bonding can radically affect the valence electron density producing large changes in chemical shift. 4/19/2017

NMR Protons attached to atoms other than carbon atoms (Con’t)
Absorption signals are frequently broad relative to other singlets, which can be used to help identify the signal. Protons attached to Nitrogen atoms often show extremely broad signals and can be indistinguishable from the base line. Typical Ranges for Groups with Variable Chemical Shifts 4/19/2017

NMR NMR Spectra at Higher Field Strengths
The 60 MHz spectrum for some compounds can be very difficult to read because the chemical shifts of several groups of protons are very similar and they overlap. Chemical shifts are dependent on the frequency of the applied radiation (or the strength of the applied magnetic field) Note: Coupling Constants (J) ARE independent. As the field strength increases, the chemical shifts of proton groups in also increase. 4/19/2017

NMR NMR Spectra at Higher Field Strengths (Con’t)
For example, a proton group resonating at 60 Hz in a 60 Mhz instrument would resonate at 100 Hz in the Mhz instrument. This effectively stretches the X-axis scale improving resolution. Note, however, the  value in ppm, does not change. 4/19/2017

NMR Chemical Shift Reagents
Interactions between molecules and solvents, such as those due to hydrogen bonding can cause large changes in resonance positions of certain types of protons, such as hydroxy (OH) and amino (NH2). Changes in resonance positions can also be affected by changing from the usual NMR solvents, such as chloroform (CCL4) and deuterochloroform (CDCl3) to solvents like benzene which impose local anisotropic effects on the surrounding molecules. In some cases a solvent change allows partially overlapping multiplets to be resolved. Most chemical shift reagents are organic complexes of the Lanthanide elements. 4/19/2017

NMR Chemical Shift Reagents (Con’t)
When added to a compound, these complexes produce profound chemical shifts, sometimes up field and sometimes downfield, depending on the metal. Europium, erbium, thulium, and ytterbium shift resonances to the lower field (higher ). Cerium, praseodymium, neodymium, samarium, terbium, and holmium shift resonances to the higher field (lower ). Another advantage of shift reagents is that shifts similar to those observed at higher fields can be induced without the need to purchase an expensive higher field instrument. The amount of the shift change depends on the distance separating the lanthanide element from the proton group and the concentration of the shift reagent. 4/19/2017

Interpreting NMR Spectra
Example 1H1 NMR Spectra Suggestions For Interpreting NMR Spectra 4/19/2017

NMR Example Spectra NMR Spectra Interpretation Procedure
The following 4 slides provide a suggested process to follow in attempting to interpret an NMR Spectra. The 1st slide is a typical NMR spectra showing 5 signals each consisting of one or more peaks. Note that each signal has a number associated with it representing the area integration, i.e., the number of protons generating the signal. Also note the expanded spectra of the signal at ppm. Expanded spectra are often provided when the signal lacks sufficient resolution to clearly display the number of peaks being generated by the protons on the carbon atom generating the signal. 4/19/2017

NMR Example Spectra The 2nd slide presents interpretations of each signal relative to the number of protons (n) on the carbon atom generating the signal and the number of protons attached to adjacent carbons atoms that produce the n+1 peaks comprising the signal as a result of “spin- spin” splitting. The 3rd slide shows how the fragments from slide 2 might fit together. The 4th slide ties it all together. 4/19/2017

 Chemical Shift () in PPM Note: Magnetic Field (Ho) increases 
NMR Example Spectra Four slides demonstrating a process for interpreting an NMR Spectra 3H  Chemical Shift () in PPM Note: Magnetic Field (Ho) increases  Slide 1 4/19/2017

NMR Example Spectra Slide 2 Doublet Triplet From chemical shifts, peak integration values, and splitting patterns, develop substructures for each signal. 3H Mono-substituted Benzene Ring Quintet Sextet 2 protons see 4 protons  5 peaks (quintet) produced 3 protons see 2 protons  3 peaks (triplet) produced 1 proton sees 5 protons  6 peaks (sextet) produced 3 protons see 1 proton  2 peaks (doublet) produced 4/19/2017

NMR Example Spectra Slide 3 Solve the Puzzle 4/19/2017

NMR Example Spectra The Solution: 2-Phenylbutane (C10H14) Slide 4 3H
3 protons on a Methyl group see 2 adjacent protons 3H triplet 3 protons on a Methyl group see 1 adjacent proton 5 protons on a mono-substituted Benzene Ring = 6 Spin-Spin Splitting No. of peaks in a signal is equal to the number of protons on all adjacent carbon atoms plus 1 (N+1 rule) doublet 2 protons on a Methylene group see 4 adjacen protons sextet quintet 1 proton on Methine group sees 5 adjacen protons Integration value (Area under signal) is proportional to No. of Protons generating the signal 4/19/2017

NMR Example Spectra Benzyl Acetate (C9H10O2) Methyl Protons (3)
No adjacent protons; no splitting Methylene Protons (2) No adjacent protons; no splitting Aromatic Protons (5) 4/19/2017

NMR Example Spectra Cyclohexene (C6H10)
3 different chemical environments Peaks actually show splitting, but is hard to see at this resolution (90Hz) b c a 4H a The “a” protons have a smaller Chemical Shift than the “b” protons because of their relative position to the electron rich  bond. The sets of 2 protons on each of the adjacent “a” carbons are equivalent and do not split each other. Each 2 proton set on an “a” carbons splits its respective adjacent 2 “b” protons to form 2 overlapping triplets. 2H c c´ a´ The single protons on the “c” carbons are equivalent; thus, they do not split each other. The single protons on each “c” carbon split the respective adjacent “b” proton to form two equal overlapping triplets b´ 4H b The 2 protons on each of the equivalent “b” carbons split their respective adjacent “protons (1 on the “c” carbon and 2 on the “a” carbon) to form two equal overlapping quartets n+1=2+1=3 (triplet) n+1=3+1=4 (quartet) n+1=2+1=3 (triplet) 4/19/2017

NMR Example Spectra 2,5-Hexanedione (Acetonylacetone) (C6H10O2) 6H
(singlet) 4H 2 Sets Methylene Protons Chemical & Magnetically Equivalent They do not split each other n+1=0+1=1 (singlet) 4/19/2017

Chemically & Magnetically Equivalent
NMR Example Spectra Cis-Stilbene (C14H12) Vinyl Protons (2) Chemically & Magnetically Equivalent Do Not Split Aromatic Protons (10) (very fine splitting) 4/19/2017

NMR Example Spectra Methyl Phenyl Acetate (C9H10O2)
Aromatic Protons (5) Methylene Protons (2) n+1 = =1 Chem Shift – 3.65 ppm Methyl Protons (3) n+1 = = 1 Chem Shift – 3.60 ppm Note: 2 Overlapping Absorptions!! Electronegative Carboxyl Oxygen forces shift of Methyl Proton absorptions downfield to about same location as shift of Methylene Protons forced downfield by effects of electronegative Carbonyl group. 4/19/2017

NMR Example Spectra 4-Heptanone (C7H14O) n+1 = 2+1=3 n+1 = 5+1=6
The Methyl & Methylene group protons on the left side of the Molecule are Chemically & Magnetically Equivalent to their counterparts on the right side, thus, the Chemical Shifts are the same and signals overlap 4/19/2017

1 proton producing Doublet
NMR Example Spectra Isopropyl Benzene (C9H12) 1 proton sees 6 protons Producing Septet n+1=6+1=7 6 protons see 1 proton producing Doublet n+1=1+1=2 6H 5H 1H 4/19/2017

NMR Example Spectra P-Nitrotoluene (C7H7NO2)
Nitro group is strongly deactivating and the Methyl group is weakly activating. The net withdrawing effect on benzene ring moves the chemical shift downfield, the Protons ortho to the Nitro group more so than The protons ortho to the Methyl group. 3H P- Dibsubstitution 4H 4/19/2017

NMR Example Spectra Phenacetin (C10H13NO2) n+1=0+1=1 (singlet) 2H 1H
(quartet) 2H 1H 3H P-Disubstitution n+1=2+1=3 (triplet) 4H 4/19/2017

NMR Example Spectra Isobutyric Acid (C4H8O2) n+1=1+1= 2 (doublet) 6H
Carboxylic Proton n+1=6+1=7 (septet) 1H 1H 4/19/2017

NMR Example Spectra 4-Amino-Acetophenone (C8H9NO) 3 2 P-Disubstitution
3 Methyl protons see 0 adjacent protons producing singlet n+1=0+1=1 Chemical Shift moved downfield because of proximity to Electronegative Carbonyl group (C=O) Withdrawing Donating 4/19/2017

NMR Example Spectra Butyrophenone (C10H12O)
The Chemical Shift of the Methylene group nearest the moderately deactivating Carbonyl group is greater than the adjacent Methylene group, because the deactivating effect diminishes with distance 3 2 Propoxyl group is moderately deactivating, deshielding “o” ring protons more so than “p” protons (aniostropic effect) “m” protons are deshielded least ortho (2) para, meta (3) 4/19/2017

NMR Example Spectra Cyclohexanone (C6H10O) a 4 b c 4 2 4/19/2017
The 4 (a) protons, probably 2 identical Methylene groups each of which is attached to a (b) Carbon with 2 protons. The net effect of these equivalent structures is that two protons see two adjacent protons producing a triplet: = 3. 4 The 4 (b) protons represent 2 identical Methylene groups each of which is attached to an equivalent Methylene group. The (b) protons also see the two (c) protons. The net effect of this is that the 4 (b) protons see effectively 2 (a) protons and 2 (c) protons producing a 4 +1 = 5 quintet. 4 The 2 (c) protons see the 4 (b) protons producing a = 5 quintet 2 Two quintets overlappiing 4/19/2017

Carbonyl carbon producing a singlet
NMR Example Spectra Isobutyl Acetate (C6H12O2) 6 2 3 Nonet Doublet Triplet Singlet 1 proton sees 8 adjacent protons producing (8+1) 9 peaks 3 protons see 0 protons on Carbonyl carbon producing a singlet 6 protons see 1 adjacent proton producing doublet 2 protons see produces doublet 4/19/2017

NMR (Carbon–13) Carbon-13 Nuclear Magnetic Resonance
Carbon-13 (13C6) possesses spin (I=1/2); thus it is a candidate for NMR Carbon-13 resonances are not easy to observe: Natural abundance of of C-13 is 1.08 % Magnetic Moment () is low Resonances are 6000 times weaker than those of hydrogen Fourier Transform instrumental techniques make it possible to observe 13C6 nuclear magnetic resonance. Chemical Shift is most useful parameter derived from 13C6 spectra. Integrals (signal areas) are Unreliable and not necessarily related to the relative number of 13C6 atoms present. Hydrogens attached to 13C6 atoms cause spin-spin splitting, spin-spin interaction between adjacent carbon atoms is rare. 4/19/2017

NMR (Carbon–13) Carbon-13 Nuclear Magnetic Resonance
The Chemical Shifts for 13C6 spectra are reported by the number of ppm ( units) that the signal is shifted downfield from TMS, just as in the proton NMR. The 13C6  scale ranges from 0 (TMS) in the upper (higher magnetic)_field to 225 ppm in the lower field. Resonance signals are more distinct providing more resolution. Adjacent CH2 carbons have distinct resonance signals. Unusual to find two carbon atoms in a molecule with the same chemical shift unless they are chemically equivalent by symmetry. 4/19/2017

NMR (Carbon–13) Coupled C-13 Spectra
In coupled C-13 NMR spectra, the spectra diagram exhibits spin-spin splitting, similar to Proton NMR, but with a significant difference The splitting pattern exhibited by a particular C-13 atom follows the N+1 rule, but the value of N is based on the number of protons attached to the C-13 atom, NOT the number of protons attached to the adjacent carbon atoms. 4/19/2017

NMR (Carbon–13) Coupled C-13 Spectra - Example (See Slide 113)
Carbons 1 Aromatic Ar 1 Benzyl CH2 1 Methylene CH2 1 Methyl CH3 1 Carboxyl O=C-O CH2 C O CH2 CH3 O Ethyl Phenyl Acetate In the coupled spectra of Ethyl Phenyl Acetate (Slide 107), the Methyl group at 14.2 ppm is split into quartet by the three hydrogen atoms attached to the carbon itself, not the protons on the adjacent Methylene (CH2) group Each quartet line is split into a triplet by the adjacent CH2 group (not seen on chart). 4/19/2017

NMR (Carbon–13) Coupled C-13 Spectra - Example (Con’t) (See Slide 113)
Carbons 1 Aromatic Ar 1 Benzyl CH2 1 Methylene CH2 1 Methyl CH3 1 Carboxyl O=C-O (See Slide 113) CH2 C O CH2 CH3 O Ethyl Phenyl Acetate Two CH2 groups The Methylene (CH2) group with the Ethyl group ( ppm) is deshielded by the adjacent O and forms a triplet because of the two attached hydrogens The Benzyl (CH2) group at 41.4 ppm is also a triplet The carbonyl appears to be a singlet at 171.1, but it is actually a triplet because of the adjacent -CH2 group (very fine, not easy to see). The aromatic ring carbons have resonances over the range of ppm. 4/19/2017

NMR (Carbon–13) Broad-Band Decoupled 13C6 Spectra
Simple molecules such a Ethyl Phenyl Acetate can yield interesting and useful structural information, namely the number of hydrogens attached to each carbon. However, for larger molecules the spectra can become very complex with overlapping splitting patterns. A broader range of 13C6 spectra can be obtained if all the protons are decoupled from the molecule by irradiating them simultaneously with a broad spectrum of frequencies in the appropriate range. 4/19/2017

NMR (Carbon–13) Broad-Band Decoupled 13C6 Spectra (Con’t)
The decoupled spectra are much simpler and easier to interpret. Each signal represents a different carbon atom. If two carbon atoms are represent by a single signal, they must be equivalent by symmetry. In the Aromatic ring of Ethyl Phenyl Acetate, the carbons at positions 2 & 6 produce a single signal, and the carbons at positions 3 & 5 also produce a single signal. 4/19/2017

NMR (Carbon–13) Carbon-13 Spectra for coupled and decoupled Ethyl Phenyl Acetate 4/19/2017

NMR (Carbon–13) Chemical Shifts for Carbon-13 NMR
Chemical Shift of each Carbon indicates its type and structural environment. As with proton NMR, electronegativity, hybridization, and anisotropy effects influence the chemical shift. Correlation Chart for Carbon-13 (ppm from TMS) 4/19/2017

NMR (Carbon–13) Carbon-13 Spectra (Proton Decoupled)
2,2-Dimethylbutane Six carbon atoms, but only 4 signals + solvent signals for CDCl3 and TMS. Single Methyl Carbon (a), signal at 8.8 ppm. Three Methyl Carbons (b) on quaternary Carbon (c), signal at 28.9 ppm. Quaternary Carbon (c), which has no hydrogens attached, appears as a small (weak) signal at ppm. Con’t on next slide 4/19/2017

NMR (Carbon–13) Carbon-13 Spectra (Proton Decoupled)
2,2-Dimethylbutane (Con’t) Methylene Carbon (d), signal at 36.5 ppm. Relative size of signals gives some idea of number of each type of carbon Note: Signal at 28.9 ppm for 3 carbon atoms. 2,2-Dimethylbutane 4/19/2017

NMR (Carbon–13) Aromatic Ring Methyl Substitution 5 Carbon Types
CH3 CH3 CH3 CH3 5 Carbon Types 3 Carbon Types 9 Carbon Types 6 Carbon Types 4/19/2017

NMR (Carbon–13) Bromocyclohexane & Cyclohexanol
A carbon atom should be deshielded by the presence of an electronegative element. The ring carbon atoms will resonate at a higher field (smaller  shift) as they are located farther away from the electronegative element Bromocyclohexane Cyclohexanol 4/19/2017

NMR (Carbon–13) Cyclohexene
Diamagnetic Anisotropy - Carbon atom attached to the double bond (c) is deshielded by the effects of the non-uniform magnetic field produced by the presence of the  electrons. Carbon atoms located farther from the double bond resonate at higher field (less chemical shift). Cyclohexene Chemical Shift (c) > (b) > (a) 4/19/2017

NMR (Carbon–13) Toluene (Hydrogen Coupled Spectrum)
Diamagnetic Anisotropy causes the carbon atom signals of the aromatic ring [ (e) > (d) > (c) > (b) ] to appear at lower field strengths (higher  values). The signal (a) for the Methyl carbon atom attached to the ring located in the higher field ( value about 22) illustrates little anisotropic effect of aromatic ring. Toluene a 4/19/2017

NMR (Carbon–13) Cyclohexanone
Strong deshielding effect of carbonyl group. The carbonyl carbon atom (d) resonates at a very low field value –  value about 211.3 4/19/2017

NMR (Carbon–13) Symmetry - 1,2- & 1,3-Dichlorobenzene isomers
A plane of symmetry for 1,2-Dichlorobenzene defines three (3) different Carbon atoms, producing three signals. A plane of symmetry for 1,3-Dichlorobenzene defines four (4) different Carbon atoms, producing four signals 1,2-Dichlorobenzene 1,3-Dichlorobenzene 4/19/2017

NMR Summary NMR Summary Notes
NMR - An instrumental technique to determine the number, type, and relative positions of certain atoms in a molecule. The technique is based on the nuclear spin properties of the nuclei of certain elements and isotopes. When the nuclei of these elements are placed in a strong magnetic field and irradiated with low energy radio waves (wavelengths of meters) they absorb energy through a process called magnetic resonance. Under these conditions the absorption of energy is quantized producing a characteristic spectrum for the compound. The absorption of energy does not occur unless the strength of the magnetic field and the frequency of the electromagnetic radiation are at specific values. 4/19/2017

NMR Summary NMR Summary Notes (Con’t)
1H1 and 13C6 have odd atomic number and/or atomic mass; thus they have spin properties and are the two primary isotopes utilized in NMR. 1H1 and 13C6 have two spins states (+1/2 & -1/2). Nuclei with +1/2 spin state align with an applied magnetic field. Nuclei with -1/2 spin state oppose magnetic field. Resonance - If radiofrequency (low energy, long wavelength) waves are applied to nuclei with spin in an applied magnetic field, the lower energy nuclei aligned with the field absorb a quantized amount of energy, reverse direction, and become opposed to the field. The stronger the magnetic field, the greater the energy absorption (resonance). 4/19/2017

An NMR instrument applies a constant radiofrequency of 60, 100, or 300 MHz and applies an increasing magnetic field strength. A higher field strength instrument allows for cleaner separation of overlapping signals, i.e., more resolution. Protons or Carbon-13 atoms of different types (chemical environments electronegativity, anisotropy, etc.) resonate at unique field strengths measured in Hertz (cycles per second) producing a signal (peak) on the chart paper. 4/19/2017

A parameter called the “Chemical Shift ()” has been defined to give the position of the absorption of a proton a quantitative value. The Chemical Shift values are report in units of “Parts Per Million” (ppm). Magnetic field, in Hertz, increases from left to right on chart scale, while  increases from right to left starting with 0 (for TMS) to 13. Protons in molecules in chemically equivalent environments will generally have the same chemical shift - one signal is produced. Observed Shift from TMS (in Hz) Hz Chemical Shift () = = = PPM 60 MHz MHz 4/19/2017

The area under an NMR signal is proportional to the number of protons generating the signal. The NMR Spectrometer electronically integrates the area under the signal. The height the of traced vertical line gives the relative numbers of each type of hydrogen. Diamagnetic Shielding - Valence electrons shield proton from applied magnetic field. Electronegative elements produce an electron withdrawing effect, deshielding the proton, resulting in a larger chemical shift, that is, a smaller magnetic field is required to induce resonance. 4/19/2017

The movement of the  electrons in aromatic rings (benzene, etc), alkenes C=, Alkynes (C), and aldehydes (O=CH) produce their own magnetic fields causing the applied magnetic field to become non- uniform (diamagnetic anisotropy), which deshields the proton increasing the chemical shift. In some cases, such as acetylenes, the effect of the anisotropic field is to shield the hydrogens, decreasing the chemical shift. Protons are affected by the presence of protons on nearby, generally adjacent, carbon atoms. Each type of proton “senses” the number of equivalent protons (n) on the carbon atom next to the one it is bonded, and splits its resonance signal into n+1 signals, a multiplet – Spin – Spin Splitting. 4/19/2017

Coupling Constant (J) - The spacing, in Hz, between the component signals in multiplet. The Coupling Constant has different magnitudes for different types of protons. Protons that have the same chemical shift and are coupled equivalently to all other protons are magnetically equivalent and do not show spin-spin splitting. For example: Protons attached to the same carbon atom that have the same chemical shift do not split each other. In monosubstituted aromatic rings, all ring protons have near identical chemical shifts resulting in a single, but slightly broader single. 4/19/2017

Electron-withdrawing (electronegative) groups, such as nitro, cyan, carboxyl, and carbonyl, deshield the ring moving the chemical shift downfield (increase ). Electron-donating groups, such as methoxy, amino, increase the electron density, moving the chemical shift up field (decrease ). Hydrogen on heteroelements - Protons on elements other than carbon, such as, oxygen (hydroxyl, carboxyl, enols), nitrogen (amines, amides) do not couple with protons on adjacent carbon atoms; thus no spin-spin splitting. 4/19/2017

Solvent effect - The absorption position in variable because these groups undergo varying degrees of hydrogen bonding in solutions of different concentrations. The amount of hydrogen bonding can radically affect the valence electron density producing large changes in chemical shift. Chemical Shift Reagents - Chloroform, Deuterochloroform, Organic Complexes of Lanthanide Elements. When added to the compound in question, these complexes produce profound chemical shifts, sometimes up field and sometimes downfield, depending on the metal. 4/19/2017

Europium, erbium, thulium, and ytterbium shift resonances to the lower field (higher ). Cerium, praseodymium, neodymium, samarium, terbium, and holmium shift resonances to the higher field (lower ). Carbon-13 NMR - 13C6 has spin and produces NMR spectra. Carbon-13 resonances not easy to observe - natural abundance 1.08 %, low magnetic moment, times weaker than those of hydrogen. Integrals (signal areas) are not reliable as indicators of the number of carbon atoms. Chemical shift scale - 0 to 200 (higher resolution). 4/19/2017

Higher resolution produces more distinctive signals making it easier to resolve signal overlapping. Unusual to find two carbon atoms with same chemical shift unless chemically equivalent. Except for a few simple molecules, 13C6 spectra can become very complex, making interpretation difficult. Irradiation of the molecules simultaneously with a broad spectrum of frequencies decouples the hydrogens from the molecule producing a much simpler spectra. Electronegativity, hybridization, and anisotropy effects influence the chemical shiftt 4/19/2017

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