Ultra High-Field NMR - American Chemical Society

2 Ultra High-Field NMR

Downloaded by UNIV LAVAL on June 14, 2014 | http://pubs.acs.org Publication Date: July 9, 1982 | doi: 10.1021/bk-1982-0191.ch002

FELIX W. WEHRLI Bruker Instruments, Inc., Billerica, MA 01821 The viability of NMR spectroscopy as an analytical tool is largely owed to the on-going development of super conducting magnet technology which has led to magnetic fields of up to 11.7 Τ with field decay rates of better than two parts in 10. A major breakthrough was the combined utilization of multifilamentary NbTi and NbSn superconductors together with jointing technolo gies providing solenoids with very small residual resis tance. Paralleling these efforts were improvements in probe technology resulting in detection sensitivities that are one order of magnitude better than those achiev able at electromagnet fields. The resolving power of such a spectrometer permits analysis of the proton spec tra of very large bio-molecules while much simplifying the multiplet structure in the spectra of complex or ganic molecules. It is further shown that increased chemical shift dispersion greatly enhances the utility of magnetic resonance of other nuclei such as C, deuterium, and many of the quadrupolar metal resonances with inherently broad lines. 8

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Nuclear magnetic resonance spectroscopy f i r s t aroused the chemist's i n t e r e s t when the d i s c o v e r y was made that the exact nu c l e a r p r e c e s s i o n frequency i s dependent upon the chemical e n v i r o n ment of the nucleus. The displacement of the resonance frequency r e l a t i v e to an a r b i t r a r y standard i s commonly r e f e r r e d to as chemical s h i f t . Without t h i s property, NMR would be without p r a c t i c a l u t i l i t y t o the chemist as an a n a l y t i c a l t o o l and i t would probably long be e x t i n c t . Since the chemical s h i f t i s d i c t a t e d by f i e l d - i n d u c e d para magnetic and diamagnetic c i r c u l a t i o n of e l e c t r o n s , i t s q u a n t i t y i s dependent upon the e x t e r n a l magnetic f i e l d o r , more a c c u r a t e l y , p r o p o r t i o n a l t o the l a t t e r . With the displacements being of the order of a few p a r t s per m i l l i o n or o f t e n only a f r a c t i o n of a p a r t per m i l l i o n , i t i s e s s e n t i a l t o conduct the experiments a t a s u f f i c i e n t l y h i g h f i e l d i n order t o r e s o l v e resonances of v a r i o u s n u c l e i p e r t a i n i n g to a molecule. 0097-6156/82/0191-0007$06.75/0 © 1982 A m e r i c a n Chemical Society

In NMR Spectroscopy: New Methods and Applications; Levy, G.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.


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Another m o t i v a t i o n to i n c r e a s e the magnetic f i e l d i s detect i o n s e n s i t i v i t y . NMR happens to be an i n t r i n s i c a l l y i n s e n s i t i v e s p e c t r o s c o p i c method, being orders of magnitude l e s s s e n s i t i v e than such methods as o p t i c a l or mass spectroscopy. When NMR was f i r s t commercialized i n 1953 i n the form of a 30 MHz instrument, i t was b a r e l y p o s s i b l e to r e s o l v e the three proton resonances p e r t a i n i n g to e t h y l alcoTiol, not even to mention s p i n - s p i n c o u p l i n g . I t was t h e r e f o r e immediately recognized that i n order to become a v i a b l e technique, the r e s o l v i n g power of the instruments had to be augmented i n terms of both magnet r e s o l u t i o n and magnetic f i e l d s t r e n g t h . The e a r l y HR-30 pioneered by V a r i a n was t h e r e f o r e r a p i d l y superseded by a 40 MHz instrument. Within f i v e years the spectrometer frequency was doubled to 60 MHz, at which stage the p o p u l a t i o n of instruments r a p i d l y i n c r e a s e d , a l though the technique remained the p r i v i l e g e of few r e s e a r c h l a b o ratories. Broader use of NMR s t a r t e d i n 1962 with the i n t r o d u c t i o n of the popular A-60, an instrument that was easy to use, r e l i a b l e and which served the s c i e n t i f i c community f o r more than a decade. With the development and i n t r o d u c t i o n of the HR-100 i n 1962, NMR r e c e i v e d a f u r t h e r impetus. The r e a l breakthrough, however, was achieved by d e p a r t i n g from the c l a s s i c a l electromagnet i n 1964, although the l a t t e r succeeded i n maintaining i t s r o l e and w i l l probably not phase out b e f o r e the mid-80's. Since s a t u r a t i o n of i r o n , which i s used as the core of electromagnets, occurs between 2.0 2.3 T, other avenues had to be explored to i n c r e a s e the c r u c i a l magnetic f i e l d . The c l u e was superconducting technology, known f o r some time but not r e a l i z e d i n the form of a h i g h - r e s o l u t i o n magnet before 1964. With the i n t r o d u c t i o n of the HR-200 during that year, s h o r t l y l a t e r followed by the HR-220, a new dimension of NMR was opened up. For the f i r s t time i t became p o s s i b l e to study high-molecular-weight s y n t h e t i c and b i o l o g i c a l molecules i n s o l u t i o n , a l l o w i n g the c h a r a c t e r i z a t i o n of these complex systems by s e p a r a t i n g some of the c l o s e l y spaced resonances which cannot be r e s o l v e d at lower f i e l d s t r e n g t h . In s p i t e of t h i s remarkable achievement, superconducting spectrometers i n i t i a l l y f a i l e d to become widely popular and they r e mained the e x c l u s i v i t y of a few high-powered r e s e a r c h l a b o r a t o r i e s . There are a v a r i e t y of reasons f o r the slow s t a r t of superconducting NMR. One of the key o b s t a c l e s , which prevented e n t r y of such s y s tems i n t o the a n a l y t i c a l l a b , was the h i g h purchase p r i c e , but more importantly, the e x o r b i t a n t o p e r a t i n g c o s t s a s s o c i a t e d with the b o i l - o f f of l i q u i d helium and n i t r o g e n which, t y p i c a l l y , had to be r e p l e n i s h e d w i t h i n a few days. Moreover, these instruments r e quired s k i l l f u l o p e r a t o r s . Remarkably, however, superconducting magnets, even i n those days, were not i n f e r i o r i n r e l i a b i l i t y to t h e i r i r o n counterparts and those e a r l y systems were put out of operation p r i m a r i l y because t h e i r u t i l i z a t i o n was no longer economically viable. The n e c e s s i t y f o r improved helium economy l e d to a new genera-


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t i o n of superconducting magnets d u r i n g the e a r l y 70's, which were f i t t e d with more e f f i c i e n t c r y o s t a t s , t h e r e f o r e p r o l o n g i n g helium and n i t r o g e n hold time. Today's c r y o s t a t s t y p i c a l l y b o i l - o f f 1020 cc of helium per hour r e s u l t i n g i n an annual helium c o s t of l e s s than $1,000 ( c f . Table I ) . Table I:

T y p i c a l annual helium consumption and a s s o c i a t e d cost f o r a superconducting magnet system between 1967 and 1980. Underlying assumption: t y p i c a l r e f i l l volume = 30 l i t e r s ; average p r i c e per l i t e r = $5.00.


YEAR 1967 1971 1975 1980

REFILL INTERVAL 3 Days 1 Week 3 Weeks 2-3 Months

ANNUAL HE COST ($) 18,000 7,500 2,600 900

With the i n t r o d u c t i o n of Bruker's HX-270 i n 1971, f i e l d s t r e n g t h r e c e i v e d another boost. At the same time i t was recogn i z e d that h i g h magnetic f i e l d s are d e s i r a b l e and o f t e n c r i t i c a l f o r the s u c c e s s f u l o b s e r v a t i o n of a number of h e t e r o n u c l e i . Superconducting instruments t h e r e f o r e became m u l t i n u c l e a r , although they were s t i l l equipped with fixed-frequency t r a n s m i t t e r s and fixedtuned probes. Within only a few y e a r s , f i e l d s t r e n g t h was f u r t h e r increased to 300 MHz i n 1973, 360 MHz i n 1974, and f i n a l l y 400 MHz i n 1978. The l a t t e r two represent another milestone s i n c e f i e l d s beyond 300 MHz proton frequency r e q u i r e r a d i c a l l y d i f f e r e n t magnet technology. In 1979, another s i g n i f i c a n t jump was made to 500 MHz proton frequency, c o n c u r r e n t l y with the i n t r o d u c t i o n of a new generation of spectrometer consoles. T h i s culminated i n the WM-500 s p e c t r o meter (1), the h i g h e s t - f i e l d commercial NMR spectrometer b u i l t so far. I t should not go unmentioned that d u r i n g the same year r e searchers at the Carnegie-Mellon I n s t i t u t e i n P i t t s b u r g h succeeded i n t a k i n g i n t o o p e r a t i o n a 600 MHz spectrometer (2) which, however, d i f f e r s i n one important aspect; i t s f i e l d i s not p e r s i s t e n t , i . e . , the magnet has to be c o n t i n u o u s l y energized to compensate f o r f i e l d decay. The e v o l u t i o n of magnetic f i e l d s t r e n g t h i n commercial NMR spectrometers over the past 15 years i s i l l u s t r a t e d by the c h a r t i n F i g u r e 1. Magnet

Technology

In order to a p p r e c i a t e the problems behind the development of the past ten years i t may be a p p r o p r i a t e to b r i e f l y review the p r i n c i p l e s and c h a r a c t e r i s t i c s of superconductors. The m a t e r i a l s which have the magnificent property of c a r r y i n g current r e s i s t a n c e - f r e e have one element i n common: they do so only at cryogenic temperatures. Table I I l i s t s the c h a r a c t e r i s t i c s of a few commercial superconductors.



Figure L Evolution of magnetic field strength (in units of the proton magnetic resonance frequency) of commercial NMR spectrometers 1953-80. Model designations: HR (Varian), HX, WH, and WM (Bruker).


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C h a r a c t e r i s t i c s of some common superconductors

Table I I :

CRITICAL TEMPERATURE

MATERIAL NbTi Nb Sn V Ga

CRITICAL FIELD at 0°K

CRITICAL FIELD at 4,,2°K

17.6 Τ 35.0 Τ 50.0 Τ

11.8 Τ 20.0 Τ 21.1 Τ

10.6 °K 18.05°K 14.5 °K

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So f a r , two p o s s i b l e routes f o r very h i g h f i e l d magnets have been pursued (_3) :


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Nb Sn Ribbon 3

The s t r e n g t h of t h i s approach i s i t s p r o v i s i o n of the highest c u r r e n t d e n s i t i e s . T h i s advantage, however, i s out weighed by a number of s e r i o u s l i m i t a t i o n s : (a) The diamagnetic c u r r e n t s generated a t the s u r f a c e of the conductor l e a d to an unstable o p e r a t i n g c o n d i t i o n w i t h unpre d i c t a b l e f i e l d / c u r r e n t r a t i o s and h i g h r e s i d u a l f i e l d s . (b) The pancake c o n s t r u c t i o n causes a discontinuous c u r r e n t path and thus higher-order f i e l d g r a d i e n t s that cannot e a s i l y be shimmed o u t . (c) J o i n i n g the tape r i n g s i s made by u s i n g soldered r e s i s t i v e j o i n t s p r e c l u d i n g p e r s i s t e n t o p e r a t i o n . In p r a c t i c e t h i s means that the c u r r e n t leads cannot be removed, causing h i g h consumption of l i q u i d helium. (2)

M u l t i f i l a m e n t Nb Sn 3

Filamentary Nb Sn wire produces h i g h homogeneity and low remanence. The smaller number of j o i n t s can be made w i t h very low r e s i s t a n c e (10~~ - 10~ ohms)(3), thus p r o v i d i n g p e r s i s t e n t operation and consequently l i t t l e helium l o s s . Nb Sn filament conductors a r e g e n e r a l l y f a b r i c a t e d by means of a s o l i d - s t a t e d i f f u s i o n process ( 4 ) . In t h i s the niobium rods are p l a c e d i n t o a bronze matrix and j o i n t l y extruded. Once the f i n a l dimension i s a t t a i n e d , the wire i s subjected to heat treatment upon which t i n s e l e c t i v e l y d i f f u s e s from the c o p p e r - t i n matrix i n t o niobium. T h i s process i s o f ten executed a f t e r s o l e n o i d winding s i n c e the h e a t - t r e a t e d wire can only to a l i m i t e d extent be mechanically deformed. 3

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The most commonly used superconductor i s NbTi, an a l l o y , which i s r e l a t i v e l y d u c t i l e , and which can be extruded i n t o wire i n a r e l a t i v e l y s t r a i g h t f o r w a r d manner. I t s t h e o r e t i c a l c r i t i c a l f i e l d at the temperature of l i q u i d helium i s 11.8 T. A more powerful superconductor i s Nb Sn, which i s superconduc3



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t i v e below 18°K with a c r i t i c a l f i e l d of 20 Τ at the temperature of l i q u i d helium a t ambient p r e s s u r e . Another superconductor which so f a r has played only an i n s i g n i f i c a n t r o l e i n superconducting magnet technology i s V$Ga. The l a t t e r two have i n common that they are i n t e r m e t a l l i c compounds that are both extremely b r i t t l e and t h e r e f o r e most d i f f i c u l t to process* An important c r i t e r i o n of a superconductor i s i t s c r i t i c a l c u r r e n t d e n s i t y , i . e . , the l i m i t i n g value of t r a n s p o r t c u r r e n t den s i t y . G e n e r a l l y t h i s q u a n t i t y i s found to decrease monotonically w i t h i n c r e a s i n g f i e l d s t r e n g t h . However, even when o p e r a t i n g below the c r i t i c a l c u r r e n t , l o c a l disturbances of v a r i o u s k i n d s may p r e vent a s t a b l e o p e r a t i n g c o n d i t i o n . I t i s t h e r e f o r e e s s e n t i a l that the conductor be s t a b i l i z e d . B a s i c a l l y t h i s i s achieved by embed ding the superconductor i n a h i g h - c o n d u c t i v i t y s u b s t r a t e m a t e r i a l ( t y p i c a l l y copper). The e f f e c t i s t h r e e f o l d : heat generated from l o c a l disturbances i s d i s s i p a t e d to the helium and the matrix mate r i a l a c t s both as a c u r r e n t bypass and f o r the a t t e n u a t i o n of f l u x p e n e t r a t i o n . A c r i t i c a l requirement of a supercon magnet i s f i e l d p e r s i s t e n c e , i . e . , the extent of decay i n f i e l d per hour. Using s p e c i a l j o i n t i n g techniques, p e r s i s t e n c i e s of 2 p a r t s i n 10 per hour have been reached r o u t i n e l y and even values up to 1 i n 1 0 (0.05 proton Hz/hour) were a t t a i n e d ( 5 ) . If a magnet f a i l s to operate i n the p e r s i s t e n t mode, i t i s r e s i s t i v e i n e i t h e r the c o i l i t s e l f , or i n the s o - c a l l e d j o i n t s , i . e . , those c r i t i c a l i n t e r f a c e s where two wires j o i n each other. J o i n t technology, i n p a r t i c u l a r where NbaSn i s concerned, i s prob a b l y the most t i g h t l y kept s e c r e t of magnet manufacturers. Oxford Instruments, L t d . , which c u r r e n t l y manufactures the highest f i e l d super-homogeneous superconducting magnet o p e r a t i n g i n the p e r s i s t e n t mode, undoubtedly owes i t s l e a d to p r e c i s e l y t h i s e x p e r t i s e . The 500 MHz e t h y l benzene spectrum i n F i g u r e 2, recorded over a 30 minutes p e r i o d i n the absence of f i e l d l o c k i l l u s t r a t e s the r e markable s t a b i l i t y of t h i s magnet ( 6 ) . For the c o n s t r u c t i o n of persistent-mode m u l t i f i l a m e n t magnets above 9.2 Τ a design strategy has been adopted i n which a background f i e l d of c a . 8 Τ i s generated by means of an outer s o l e n o i d c o n s i s t i n g of NbTi m u l t i f i l a m e n t wire, wound on an aluminum former and potted i n a b i n d i n g matrix to prevent wire movement. I n s i d e t h i s c o i l a Nb3Sn i n s e r t c o i l i s p l a c e d that i s run i n s e r i e s with the outer s o l e n o i d . Another major challenge i n supercon magnet technology i s achievement of f i e l d u n i f o r m i t y . I t should f o r example be borne i n mind that i n order to o b t a i n a given l i n e width a t 500 MHz r e q u i r e s a 5 times b e t t e r f i e l d homogeneity than at 100 MHz spectrometer f r e quency. R e a l i z a t i o n of say 0.1 Hz proton r e s o l u t i o n , a value which has been achieved and surpassed, t h e r e f o r e demands the utmost i n terms of workmanship and q u a l i t y of m a t e r i a l . T h i s concerns, among other f a c t o r s , constancy of wire diameter and u n i f o r m i t y of winding. In s p i t e of these p r e c a u t i o n s , such ambitious o b j e c t i v e s n e c e s s i t a t e v a r i o u s forms of f i e l d c o r r e c t i o n s , whose d e t a i l e d d i s c u s s i o n however, would break the scope of t h i s a r t i c l e . 8

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PPM F/gwré? 2. /I 500-MHz proton spectrum of 0.01% ethylbenzene standard, recorded over a 30 min total accumulation time in the absence of field/frequency lock. Inset shows expanded methyl triplet (6).


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The r e s o l u t i o n and l i n e shape t e s t s p e c t r a i n F i g u r e s 3a and b obtained a t 500 MHz demonstrate that a l e v e l o f performance has become f e a s i b l e that u n t i l r e c e n t l y was unachievable even a t a con s i d e r a b l y lower f i e l d . Obtainment of t h i s degree o f f i e l d u n i f o r mity i s c r u c i a l , however, i f the b e n e f i t o f enhanced s h i f t separa t i o n i s to be f u l l y e x p l o i t e d .


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The magnet, though the heart of the spectrometer, i s not the only component that puts h i g h e r demands on i t s performance. A p a r t i c u l a r c h a l l e n g e , f o r example, i s probe technology, both i n terms of observation and decoupling, s i n c e a t 500 MHz one approaches the frequency range which i s midway between r a d i o frequencies and microwaves. T h i s l e d to h y b r i d c a v i t y resonators which have suc c e s s f u l l y been used f o r both proton observation and proton h e t e r o n u c l e a r broadband decoupling. Outstanding s e n s i t i v i t y can be ob t a i n e d by t h i s approach. The S/N r a t i o of 20:1 on 0.01% e t h y l ben zene, r e c e n t l y achieved on a WM-500 spectrometer, i s n e a r l y two orders o f magnitude b e t t e r than that of a 1970 v i n t a g e electromag net system, thus p r o v i d i n g access to experiments on e i t h e r extremely small sample q u a n t i t i e s (submicrogram) o r a t very low concentra t i o n s (10~" -10~ molar). A number of a d d i t i o n a l requirements a r e r e l a t e d to the i n creased s p e c t r a l windows demanding f a s t e r ADC's, l a r g e r data memo r i e s and d i s k storage c a p a c i t i e s and, i n order t o ensure uniform e x c i t a t i o n across the f u l l spectrum, increased pulse power. A 200 ppm F spectrum, f o r example, a t 11.7 Τ i s n e a r l y 100 KHz wide, thus r e q u i r i n g sampling a t 200 KHz. The a c h i e v a b l e r e s o l u t i o n under such circumstances i s almost c e r t a i n l y not l i m i t e d by magnet homo geneity but r a t h e r by data memory. From the data i n Table I I I , i t can be i n f e r r e d that a t 11.7 Τ a 250 ppm C spectrum r e q u i r e s a t l e a s t 128 Κ of data memory i n order to o b t a i n a d i g i t a l r e s o l u t i o n of .5 Hz. Although the c o s t of computer memory has s t e a d i l y de creased over the past y e a r s , i t may be of b e n e f i t t o enhance d i g i t a l r e s o l u t i o n i n other ways than by adding memory c h i p s . T h i s can, f o r example, be r e a l i z e d by s t o r i n g the acquired data p o i n t s onto d i s k during the dwell time, i . e . , the i n t e r v a l between two d i g i t i z e r samples. T h i s s o - c a l l e d v i r t u a l memory c a p a b i l i t y allows one to a c q u i r e very l a r g e data t a b l e s and i t s only l i m i t a t i o n l i e s i n spec t r a l width s i n c e the maximum r a t e a t which data can be sampled and stored i s d i c t a t e d by the d i s c t r a n s f e r r a t e . For a modern h i g h speed d i s c d r i v e , t r a n s f e r r a t e s are such that i n the d i s c a c q u i s i t i o n mode s p e c t r a l widths o f t y p i c a l l y 50 KHz have become f e a s i b l e , which i s adequate f o r most h i g h - r e s o l u t i o n a p p l i c a t i o n s . The poten t i a l of t h i s approach i s e x e m p l i f i e d by the u l t r a - h i g h - r e s o l u t i o n spectrum of e t h y l benzene i n F i g u r e 4 obtained by d i s k a c q u i s i t i o n of 256 Κ data p o i n t s (6). In t h i s remarkable spectrum almost a l l of the aromatic protons are completely separated, showing l o n g range couplings between methylene and r i n g protons. 5

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Figure 3a.

Λ 500-MHz lineshape test showing chloroform line width at a height and at a height 1/5 thereof. Recorded on a 5-mm o.d. sample.



Figure 3b. A 500-MHz resolution test showing the high-frequency half of the o-dichlorobenzene signal. Recorded on a 5-mm o.d. sample.


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Figure 4a. A 500-MHz proton NMR spectrum of 1% ethylbenzene obtained by in-core acquisition and transformation of 32 Κ data points without further data manipulation. Inset shows expansion of aromatic region.

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Figure 4b. Aromatic portion of the spectrum of the same sample recorded by disk acquisition and transformation of 128 Κ data points using a total of 48 Κ hardware memory. Resolution was further enhanced by Lorentz-Gauss transformation (6).

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Table I I I : Data memory requirements f o r a d i g i t a l r e s o l u t i o n of 0.5 Hz across a 250 ppm C spectrum a t d i f f e r e n t spectrometer f r e q u e n c i e s . 1 3

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2.3 5.7 11.7

A

H FREQUENCY (MHz)

MEMORY CAPACITY (K WORDS) 32 64 128

100 250 500

The transformation time of such l a r g e data s e t s becomes of the order of minutes, e v e n t u a l l y i n v o k i n g hardwired F o u r i e r transform p r o c e s s o r s . Although c u r r e n t l y not i n use on any commercial NMR spectrometers, array processors are expected to supersede F o u r i e r transformation by software over the next few y e a r s . Concomitant w i t h the increased data s i z e , the memory r e q u i r e ments f o r permanent storage w i l l render i t necessary t o expand the storage c a p a c i t y of backup s t o r e s . D i s k storage c a p a c i t i e s of over 100 M-byte, as they have become a v a i l a b l e i n the form f o r example of the CDC 9730 S e r i e s , are a true n e c e s s i t y i n many h i g h - f i e l d NMR a p p l i c a t i o n s . Memory requirements are p a r t i c u l a r l y severe i n twodimensional spectroscopy such as the 2D-J experiments where s p e c t r a l a r r a y s are obtained i n which s p i n - s p i n c o u p l i n g i s separated from chemical s h i e l d i n g . A 10 ppm χ 50 Hz 2D spectrum w i t h a d i g i t a l r e s o l u t i o n of 2 Hz on the 6 a x i s and 0.2 Hz on the J a x i s , f o r ex ample, corresponds to a 4 M-word data matrix. An a d d i t i o n a l consequence of the widened s p e c t r a l windows a t high spectrometer f i e l d i s the requirement f o r enhanced pulse power. In order to assure uniform e x c i t a t i o n across the f u l l s p e c t r a l width the r f p u l s e s have to be s u f f i c i e n t l y s h o r t . T h i s i s p a r t i c u l a r l y c r i t i c a l to achieve w i t h high-Q m u l t i n u c l e a r probes, and a f u l l y s a t i s f a c t o r y s o l u t i o n to t h i s problem has a t t h i s time not been found. In F i g u r e 5 the t r a n s m i t t e r r f amplitude d i s t r i b u t i o n f o r a 25 microsecond p u l s e i s i l l u s t r a t e d f o r a 250 ppm C spectrum at three d i f f e r e n t f i e l d s t r e n g t h s , showing only minimal droop across the spectrum at 2.3 Τ but a c o n s i d e r a b l e f a l l - o f f a t 11.7 T. In p r a c t i c e , t h i s problem i s a l l e v i a t e d s i n c e r e l a x a t i o n o f t e n demands pulse f l i p angles that are c o n s i d e r a b l y l e s s than 90°. Moreover, i t turns out that the f a l l - o f f of r f amplitude i s l a r g e l y o f f s e t by the increased e f f e c t i v e r f f i e l d that e x i s t s a t f r e q u e n c i e s more remote from the c a r r i e r . 1 3

Typical Applications C l e a r l y the greatest b e n e f i t s of very h i g h magnetic f i e l d are expected i n proton spectroscopy o f l a r g e b i o l o g i c a l molecules such as p e p t i d e s , p r o t e i n s , n u c l e i c a c i d s , e t c . Organic chemists however, who have s t r u g g l e d w i t h the a n a l y s i s of proton s p e c t r a of n a t u r a l products and t h e i r s y n t h e t i c analogs w i l l agree that the s p e c t r a o f r a t h e r low-molecular weight molecules (MW 200-500) may be e n t i r e l y


In NMR Spectroscopy: New Methods and Applications; Levy, G.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982. 13

Figure 5. amplitude distribution across a 250-ppm C NMR spectral window for a 25-ps excitation pulse at three different magnetic field strengths. Percentage numbers indicate total variation of amplitude.


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u n i n t e r p r e t a b l e unless nature has b l e s s e d them with at l e a s t one or s e v e r a l e l e c t r o n e g a t i v e s u b s t i t u e n t s or m u l t i p l e bonds. In t h i s unfortunate but r a t h e r common s i t u a t i o n two dozen m a g n e t i c a l l y nonequivalent protons may t y p i c a l l y be squeezed i n the r e g i o n between 1 and 2.5 ppm. Not only are such s p e c t r a h i g h l y second order, but worse, t h e i r i n d i v i d u a l m u l t i p l e t s are mutually overlapping. The expert NMR s p e c t r o s c o p i s t r a p i d l y concludes i n such a s i t u a t i o n that any f u r t h e r e f f o r t i s a waste of time. Figure 6 i l l u s t r a t e s the power of 500 MHz H NMR of a medium-sized molecule (7) . Among the 18 m a g n e t i c a l l y nonequivalent groups of protons i n g u a j o l (MW= 222), 16 give r i s e to separated m u l t i p l e t s i n s p i t e of t h e i r t o t a l resonance range of only 1.6 ppm. F i g u r e 6b shows the expanded spectrum f o l l o w i n g a Lorentz-Gauss transformation of the f r e e induct i o n decay, a l l o w i n g e x t r a c t i o n of three and more d i f f e r e n t s p i n s p i n c o u p l i n g constants per m u l t i p l e t . The highest f i e l d proton, f o r example, shows c o u p l i n g constants of 13.5 Hz (geminal), 10 Hz ( v i c i n a l a x i a l - a x i a l ) and 5 Hz ( v i c i n a l a x i a l - e q u a t o r i a l ) . Assuming the C-4 s u b s t i t u e n t to be e q u a t o r i a l l y disposed, t h i s proton has to be assigned to e i t h e r H ( 2 ) or H(3)ax s i n c e the m u l t i p l i c i t y p a t t e r n shows two equal e q u a t o r i a l i n t e r a c t i o n s and one each of the a x i a l - a x i a l and geminal type. Since assignment of H ( l ) i s s t r a i g h t forward, a s i n g l e double resonance experiment would e l i m i n a t e t h i s ambiguity and at the same time corroborate the stereochemistry at C ( l ) or C(4). Among the many a p p l i c a t i o n s of the technique, C NMR has been found to be the method of choice f o r the c h a r a c t e r i z a t i o n of synt h e t i c polymers such as sequence a n a l y s i s , end group determination and e l u c i d a t i o n of s t e r e o r e g u l a r i t y i n v i n y l polymers. In a v i n y l polymer, f o r example, the CH s h i e l d i n g i n the -CHX-CH2- r e p e a t i n g u n i t depends upon the c o n f i g u r a t i o n of the asymmetric carbon of i t s neighbors and nearest neighbors. I f only nearest neighbors can be d i s t i n g u i s h e d , t r i a d s p l i t t i n g s are observed, according to the stereochemical d i s p o s i t i o n s mm (meso meso), mr, rm (meso racemic or i t s i n d i s t i n g u i s h a b l e racemic meso) and r r . I f next nearest i n t e r a c t i o n s can be d i f f e r e n t i a t e d , s o - c a l l e d pentad s p l i t t i n g s r e s u l t (maximum 10). Increased f i e l d c l e a r l y augments the c a p a b i l i t y of r e s o l v i n g t h i s f i n e s t r u c t u r e and the spectrum of a t a c t i c poly ( v i n y l c h l o r i d e ) i n 1,4-dioxane i n F i g u r e 7 (8) shows evidence of heptad f i n e s t r u c t u r e , i . e . , l i n e s r e s u l t i n g from c o n t r i b u t i o n s of r e p e a t i n g u n i t s i n t h i r d p o s i t i o n r e l a t i v e to the carbon observed. In t h i s case, 16 out of the t h e o r e t i c a l 36 observâtionally d i f f e r e n t heptads could be f u l l y r e s o l v e d . Another nucleus of c o n s i d e r a b l e a n a l y t i c a l p o t e n t i a l i s deuterium, whose observation at n a t u r a l abundance has been demonstrated e a r l i e r (9) but whose p r a c t i c a l i t y has so f a r been s e v e r e l y l i m i t e d due to i t s low NMR r e c e p t i v i t y and a l s o because of i t s more than s i x times smaller chemical s h i f t range r e l a t i v e to the proton. These l i m i t a t i o n s are l a r g e l y overcome at h i g h magnetic f i e l d as i l l u s t r a t e d by the natural-abundance deuterium s p e c t r a of camphor i n F i g u r e 8. By l i n i n g up the proton-decoupled deuterium spectrum with the


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In NMR Spectroscopy: New Methods and Applications; Levy, G.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982. 1

Figure 6a. A 500-MHz H full spectrum of guajol with partial assignments. Resolution in this spectrum was further enhanced by a Lorentz-Gauss transformation of the free induction decay (7).



Figure 6b. 500-MHz *H spectrum of guajol with partial assignments. Region between 1.3 and 1.8 ppm expanded. Resolution in this spectrum was further enhanced by a Lorentz-Gauss transformation of the free induction of decay (7).



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Figure 7. A 125.8-MHz C NMR spectrum of the methane carbon region in polyvinyl chloride, 10% in 1,4-dioxane-d at 370 K. Configurational assignments are based on the relative triad inten sities assuming Bernoullian statistics ($).

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Figure 8. A, A 360-MHz proton NMR spectrum of camphor, 2 M in deuterochloroform; Β and C, A 55-MHz natural-abundance H NMR spectrum of the same sample with (B), and without (C) proton broadband decoupling. 2


N M R SPECTROSCOPY

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r e s p e c t i v e proton spectrum on the same ppm s c a l e (Figures 8a andb) the 1:1 correspondence of the two s p e c t r a becomes apparent. Highr e s o l u t i o n deuterium NMR s p e c t r a may t h e r e f o r e be drawn upon to e s t a b l i s h chemical s h i f t s i n complex proton s p e c t r a to provide a set of s t a r t i n g parameters f o r computer-aided s p e c t r a l a n a l y s i s . Further d i a g n o s t i c information may be derived from the protoncoupled deuterium spectrum as i l l u s t r a t e d i n F i g u r e 8c showing m u l t i p l e t s due to geminal H- H c o u p l i n g ; f o r example t r i p l e t s f o r methyl groups and doublets f o r the s i g n a l s due to the i s o l a t e d hydrogens H(2)eq and H ( 2 ) . Other m u l t i p l e t s remain unresolved s i n c e the geminal couplings are obscured by v i c i n a l and long-range c o u p l i n g . As quadrupole r e l a x a t i o n dominates deuterium r e l a x a t i o n , h i g h r e s o l u t i o n H NMR i n l i q u i d s w i l l be confined to small and mediums i z e d molecules where r e l a x a t i o n broadening i s moderate. Assuming f o r example a c o r r e l a t i o n time of 1 0 sec as i t i s t y p i c a l of a molecule of MW - 250, a n a t u r a l H l i n e width of 1.5 Hz r e s u l t s based upon a quadrupole c o u p l i n g constant of 180 kHz. A somewhat e s o t e r i c a p p l i c a t i o n of deuterium NMR, which i s t o t a l l y outside the realm of the p o s s i b l e at low f i e l d concerns the determination of the anisotropy of the diamagnetic s u s c e p t i b i l i t y . T h i s experiment, f i r s t suggested by Dutch workers MacLean and Lohman, (10) i s based upon the f a c t that the s t a t i c quadrupole s p l i t t i n g may not be t o t a l l y averaged due to p a r t i a l alignment of the molecule at h i g h magnetic f i e l d s t r e n g t h . While d i p o l a r s p l i t t i n g s are too small to be r e t a i n e d during motional averaging, the quadrup o l a r i n t e r a c t i o n i s l a r g e enough to be d e t e c t a b l e at f i e l d s above ca. 9.2 T. F i e l d strength i s c r i t i c a l since the s p l i t t i n g s are prop o r t i o n a l to the square of the magnetic f i e l d . F i g u r e 9 shows the resolution-enhanced 77 MHz (11.7 T) deuterium spectrum of nitrobenzene d i s p l a y i n g quadrupole s p l i t t i n g s f o r a l l three magnetically nonequiv a l e n t deuterons (11). There are many more n u c l e i whose p o t e n t i a l cannot be e x p l o i t e d unless the chemical s h i f t s are d i s p e r s e d beyond the l i n e widths. T h i s holds true f o r the great d e a l of quadrupolar n u c l e i which cons t i t u t e the bulk of the magnetic n u c l e i i n the P e r i o d i c Table and which play an important r o l e i n i n o r g a n i c chemistry. The u t i l i t y of h i g h magnetic f i e l d i n t h i s area may be i l l u s t r a t e d with an example from i n o r g a n i c s o l u t i o n chemistry, r e l a t e d to some recent work i n t h i s l a b o r a t o r y d i r e c t e d toward the charact e r i z a t i o n of the s o l u t i o n species formed upon d i s s o l v i n g the a l u minum h a l i d e s i n p o l a r organic s o l v e n t s (12). While, f o r a long time, i t was assumed that i n p o l a r s o l v e n t s the dimeric A I 2 C I 6 breaks up i n t o A l C l i f " and A 1 S 6 (S = a c e t o n i t r i l e ) , t h i s view was r e c e n t l y challenged (13) as a r e s u l t of the A 1 s p e c t r a which suggest the e x i s t e n c e of mixed species [ A l C l S 6 _ ] 3 ~ . However, c o n c l u s i v e evidence was only provided by experiments at high f i e l d . F i g u r e 10 shows a stacked p l o t of 93.7 MHz A 1 NMR s p e c t r a of A I C I 3 i n a c e t o n i t r i l e recorded at d i f f e r e n t solute concentrations. These s i g n a l s are due to above-mentioned hexacoordinated s o l v a t e / c o u n t e r i o n complexes which could be i d e n t i f i e d on the b a s i s of c h a r a c t e r i s t i c chemical s h i f t s and p r e d i c t a b l e 2

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Figure 9. A 76.8-MHz resolution-enhanced deuterium NMR spectrum of neat nitrobenzene showing quadrupole splittings due to partial alignment resulting from anisotropy of diamagnetic susceptibility. (Reproduced, with permission, from Ref. 11. Copyright 1981, Academic Press.)


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Figure 10. High-field Al NMR spectra of aluminum chloride in acetonitrile solu tion showing the resonance region of hexacoordinated Al. Peak designations: 1, Al(CH CN) ; 2, [AlCl(CH CN) ] +; 3, c\sr[AlCl (CH CN)J*; 4, tranS'[AlClg(CH CN)t] ; 5, cis-AlCl (CH CN) ; 6, trans-AlCl (CH CN) , and 7, cis/trans[AlCl (CH CN)zY. (Reproduced with permission, from Ref. 12. Copyright 1981, Academic Press.) 27

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quadrupole r e l a x a t i o n r a t e s . The c l o s e l y spaced l i n e p a i r s 3/4 and 5/6, f o r example, r e f l e c t the e f f e c t of c i s / t r a n s isomerism i n [AICI2S1J" " and A I C I 3 S 3 which would c l e a r l y be u n r e s o l v a b l e i f the f i e l d s t r e n g t h were halved. In c o n c l u s i o n , i t may be stated that NMR a t very h i g h f i e l d has given the technique an unprecedented impetus. As a consequence of the enhanced s h i f t s e p a r a t i o n the s p e c t r a l i n f o r m a t i o n content has been g r e a t l y increased, opening up a range of new experiments. Together w i t h the concomitant s e n s i t i v i t y increase t h i s w i l l have a s i g n i f i c a n t impact on a v a r i e t y of r e s e a r c h areas, notably molecular b i o l o g y , macromolecular chemistry, but a l s o organic and i n o r g a n i c chemistry i n g e n e r a l .


1

LITERATURE CITED 1. Bruker Report 3/1979. 2. 600 MHz Symposium at Carnegie-Mellon Institute, 1979. 3. McDonald, P. & Proctor, W., Proceedings of the Eighth Inter national Cryogenic Engineering Conference, 1980, p. 509. 4. Kwasnitza, Κ., Narlikar, A.V., Nissen, H.U., & Salate, D., Cryogenics 20, 715, 1980. 5. Hull, W. E., personal communication. 6. Hull, W. E., personal communication. 7. Formacek, V., personal communication. 8. Elgert, K.F., Kosfeld, R., & Hull, W.E., personal communication. 9. Shoolery, J.N., Varian Application Topic, 1977, p. 7-14. 10. Lohman, J.A.B., & MacLean, C., Chem. Phys., 1978, 35, p. 269; 1979, 43, 144. 11. Lohman, J.A.B., MacLean, C., J. Magn. Res., 1981, 42, p.5. 12. Wehrli, F.W. & Wehrli, S.L., J. Magn. Res., 1981, 44. 13. Akitt, J.W. & Duncan, R.H., J. Magn. Res., 1977, 25, 391. RECEIVED February 2, 1982.


Ultra High-Field NMR - American Chemical Society

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