high performance sector mass spectrometers: past and present

~~ ~~~ ~

High performance sector mass spectrometers: past and present

Takekiyo Matsuo lnstitute of Physics, College of General Education, Osaka University, Toyonaka, Osaka (560) japan

I. INTRODUCTION

This article is based on the author’s plenary lecture at ASMS in San Francisco in 1988. The author is grateful to the American Society for Mass Spectrometry for inviting him to the conference and for giving him the opportunity to present a lecture on the development of high performance mass spectrometry.

The report is divided into the following sections.

1. Definition of High Performance Mass Spectrometers 2. Development of Mass Spectrometer Design: Past ”High Performance

3. What are TODAY’S ”High Performance Mass Spectrometers” Mass Spectrometers”

At this point, I propose to classify mass spectrometrists into three main groups and, hopefully, explain the structure of this article:

First, there are those who employ mass spectrometry as an analytical tool simply because of its suitability. The salient point for them is not the instrument itself, but the output in the form of precise data indicating mass number and relative intensity. These are the people who influence the growth of mass spectrometry.

Second, there are those who are keen to acquire the mass spectra of novel compounds and interpret them accordingly. These people have contributed greatly to elevate mass spectrometry to its current high status in chemical analysis.

Third, there is another group whose principal interests lie in the instrumental hardware, developing new machines and related techniques.

My own speciality consists of 10% from the first category, 20% from the second, and 70% from the third. Although most of present mass spectrometrists fall into the first category, I ask that the reader allow me the liberty of writing from my own viewpoint. As you know, several independent mass spectrometer systems based on different principles are in general use: sectors, quadrupoles, time-of- flight, and Fourier transform ion cyclotron resonance (FT-ICR), etc. I will limit my discussion to sector instruments, as I have experience in these areas. A very

Mass Spectrometry Reviews 1989, 8, 203-236 0 1989 John Wiley & Sons, Inc. CCC 0277-7037/89/040203-34$04.00

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elegant and inspiring lecture on the comparison of recent different type instruments was given by Brunnee (1).

11. DEFINITION OF A HIGH PERFORMANCE MASS SPECTROMETER

Thlrty years ago, in 1958, the Consolidated Electrodynamics Corporation‘s group of California, presented a report entitled ”Theoretical And Experimental Study of High-Mass, High-Resolution Mass Spectrometers” at the conference held in London and published the presentation in the first edition of Advances in Mass Spectrometry (2). In this review, the term ”High-performance mass spectrometer” was used to the best of my knowledge for the first time. Since then, this expression has been used to describe a mass spectrometer which possesses some of the following features:

1. Capability of high mass resolution, high sensitivity and high mass range 2. Multiple ion sources (GC, LC, MS) and single or simultaneous detectors 3. Multiple operation including positive or negative mode and normal or

The three statements may be the ”standard” definition of a high-performance mass spectrometer. We may call a mass spectrometer that possesses some of such characters a high performance mass spectrometer.

My personal opinion is that this term is more often applied to a commercial apparatus rather than the more deserving prototype instruments. A high-performance mass spectrometer may also be termed a ”high-grade multipurpose mass spectrometer,” or, more jokingly, a ”greedy mass spectrometer.”

In this article, I would like to elaborate on my “personal” definition of a high- performance mass spectrometer. For this purpose, I am going to compare the evolution of mass spectrometers with dynamic problems encountered in physics. The problems of physics, mainly dynamics, can be represented in cases of increasing complexity. We start by looking at a one-dimensional problem, then at two-, three-, four-, and n-dimensional cases. I will try to explain these relation- ships with a simple series of illustrations:

linked scan

A. One-dimensional problem

A spring vibrating in one dimension is a simple case (see the left side of Fig. 1). This is the simplest pattern of movement in the world, and can be called a one-dimensional problem. Most physics problems begin with this simple case. The Berzelius’s balance, the first instrument that was used to determine accurately atomic and molecular weights, is given on the right side of Figure 1. It was around 1820, in Sweden, that Berzelius determined the atomic weight of 45 elements. It is interesting that the atomic mass numbers determined by him agree quite well with today’s values-to within a percent accuracy. Present mass numbers based on l6O = 16 are shown in order to compare them with Berzelius’s data. Note that the information given by him was numerical with no information pertaining

HIGH PERFORMANCE SECTOR MASS SPECTROMETERS 205

ONE DIMENSIONAL PROBLEM BERZELIUS’S BALANCE

C 12.23 11.01

N 11.16 im

0 16.00 I6.W

Figure 1. The one-dimensional problem.

to atomic or molecular structure. This is why I compare Berzelius’s balance to a one-dimensional problem.

Electron’s Mass (Digression): Although I do not show it in Figure 1, the electron mass is also a one-dimensional problem with many implications. Thomson had applied the method of determining the electron mlz value to the positive ray, and Dempster used the technique to measure electron energy by using a magnetic field in his positive ray analysis. The strategy of characterizing the “electron” was applied to study “positive rays.” Although the electron mass approximately equals only one two thousands of that of the proton, the electron problem might be ”ancestor” of mass spectrometry. I would like to add one limit of today’s theoretical physics concerning the electron mass. The electron mass consists of “rest mass,” which means the mass of electron under the assumption that charge is stripped off and of “electromagnetic mass,” which is the sum of electromagnetic energy filled in space. The latter concept was already introduced by Thomson in 1891. The sum of them, namely the electron mass, was determined by Thomson (3) . Individual masses cannot be determined, however, because nobody can determine the precise radius of electron even after the success of ”renormalization theory” by S. Tomonaga, J. Schwinger, and P. Feynman (4). The problem of ”electron mass” was the first and, at the same time, the last one.

B. Two-dimensional problem

A pendulum clock (see the left side of Fig. 2) is an example of two-directional movement, with the position of the pendulum being describable by x and y coordinates. A mass spectrum (see the right side of Fig. 2) is shown in a two- dimensional plane where we can represent information relating to the mass num-

1 rn - 3300 3400 3500 M/Z

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Glucagon

TWO DIMENSIONAL PROBLEM MASS SPECTRUM

Figure 2. The two-dimensional problem.

( M + H ) + 3482

ber and ion intensity. The mass number is related to the abscissa, and the ion intensity to the ordinate.

C. Three-dimensional problem

The phenomena of normal daily movement is usually represented in three- dimensions. For example, airplanes leaving San Francisco airport traveling (see the left side of Fig. 3) to various airports via various routes are described in a three coordinate system. The right side of Figure 3 is an example of a three- dimensional mass spectrum (5): the three coordinates being mass number, ion intensity, and time. This is the type of spectrum we could expect from a gas chromatography-mass spectrometry (GUMS) or LC/MS experiment. If the third coordinate is mass number again, this can represent an MSiMS spectrum.

In physics, the four-dimensional world is commonplace; introduced in 1908 as Minkowski's space time theory, it has particular pertinence in the theory of rel- ativity. Nowadays, elementary particle theoreticians have introduced a tenth dimensional concept in the super string theory (6). It is not easy, however, to represent this concept as a simple figure. The high-performance mass spectrometers of the future may produce four-dimensional mass spectra. Thus, I am looking forward to encountering the mass spectrometers of the 21st century.

Now, I would like to return to the subject and to give my "personal" definition to the term high-performance mass spectrometer based on the above comparisons. High-performance mass spectrometers in the past provided two-dimensional mass spectra. Today's high-performance mass spectrometers provide three-dimensional mass spectra. Three-dimensional mass spectra will be discussed later in detail.

HIGH PERFORMANCE SECTOR MASS SPECTROMETERS

THREE DIMENSIONAL PROBLEM

THREE DIMENSIONAL MASS SPECTRUM

Figure 3. The three-dimensional problem.

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111. DEVELOPMENT OF MASS SPECTROMETER DESIGN: "HIGH-PERFORMANCE MASS SPECTROMETERS" OF THE PAST

I will review the following famous instruments quickly to give an idea what were past high-performance mass spectrometers from the following viewpoints,

1. The purpose of development 2. The background knowledge 3. The innovations 4. The results 5. The limitations of the instruments

A. The background of the birth of the mass spectrograph: vacuum discharge

"Vacuum discharge" or to give an exact translation "artificial thunder," trig- gered the development of the mass spectrograph at the turn of the 20th century. As a high school student, I witnessed a vacuum discharge experiment that sur- prised and impressed me. That original excitement of seeing light in a vacuum remains with me to this day, so I can easily imagine the excitement of the scientists of the past and their desire to investigate the substances that caused the unknown ray. The phenomenon of vacuum discharge was systematically investigated by Faraday and Davy in 1822, based on the former experiments by J. Walsh and W. Morgan. More than ten famous scientists (e.g., Goldstein, Wien) had tried to unmask the true character of the unknown materials. In those days, even the distinction whether the unknown ray was "particle" or "wave" was not clear. They brought understanding to the unknown ray slowly but steadily. Such steady scientific efforts had acted as forerunners for the quantum mechanical leap of knowledge. The understanding led to the birth of a mass spectrograph in the field we know today.

B. Thornson's parabola analyzer

Thomson recognized that the unknown ray consisted of charged corpuscles (electrons), although Roentgen had succeeded in the discovery of "x-rays." The success of Roentgen's experiments meant that the concept of "wave" might be superior to that of "particle." It should be noted that early researchers like Roent- gen and Thomson were able to detect only one or the other of the two aspects of small particles. Despite this, Thomson persevered in characterizing charged corpuscles. Finally, Thomson succeeded in determining the mass-to-charge ratio of the electron by the use of electric and magnetic deflection ( 3 ) . After this success, he tried to analyze "positive rays" by using the techniques developed for determination of the electron mass and constructed the parabola analyzer (7). Thomson was indeed the father of modern mass spectrometry. Both theoretically and prac-

tically, his research on positive ray analysis was marvelous, but he was less interested in mass spectrometry than in pursuing the electron.

C. Aston’s mass spectrograph

In 1910, Aston was invited to join Thomson at the Cavendish at Cambridge University and soon made advances with Thomson’s parabola apparatus. Using his expertise in high vacuum technology, Aston introduced the large low-pressure discharge bulbs (ion production) and also designed the kind of camera that became standard for photographing the parabolas (detection). He obtained the first pic- tures of the twin parabolas of neon in 1912. Aston constructed an improved apparatus for separating isotopes by velocity focusing (mass separation). The new instrument, which he called the ”mass spectrograph,” had vast improvements in beam intensity, beam dispersion, and resolving power. The performance of the instrument was very impressive, and the atomic weights of almost all the elements known at that time were determined by using this instrument (8).

I believe that we can say that Aston’s instrument was really the first high- performance mass spectrograph according to the “standard” definition. Aston was the first scientist who worked in all three areas of mass spectrometry research: ion production, mass separation, and detection.

D. Dempster’s mass spectrometer

Almost at the same time in the United States, Dempster was involved in the development of a mass spectrometer for quantitative analysis by measuring ion current directly. He also entered into mass spectrometry through the electron. He applied the method of determining the energy of the electron by using the direction focusing action of a homogeneous magnetic field to positive ray analysis (mass separation). He also developed a method to measure the ion current directly by using an electrometer (detection). He was less interested in ion production, however. In his article “A New Method of Positive Ray Analysis,’’ published in Physical Review in 1918 (9), he introduced the standard format of articles concerning mass spectrometry. He stated that “The only experimental difficulty is to get the rays, and this is the matter now under investigation.’’ This statement expressed that he was worried about ion production. Even today, this pillar is the most difficult one among three pillars of mass spectrometry.

E. Bainbridge-Jordan’s mass spectrograph

The principle of “double focusing” received the simultaneous but independent attention of several investigators. A complete theory of all the arrangements of a radial electric field and an homogeneous magnetic field-for which both direction and velocity focusing could be obtained-was published by Herzog (and Mattauch) in 1934 (10). Immediately after its publication, two teams in the United States constructed machines by using the double focusing principle: Dempster in

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Chicago and Bainbridge at Harvard. At this time, the term "tandem mass spectrometer" was first used for an apparatus consisting of electric and magnetic fields in series. The Bainbridge-Jordan instrument was the first to be used for precise determination of atomic masses (11).

Around this time (1938), a similar set-up was constructed by Asada at Osaka University, signaling the initiation of the Japanese into the field of mass spectrometry. Mass resolution of 10,000 was obtained (12). This instrument has a special meaning for me because the spirit of constructing a mass spectrograph a half century ago still runs in my blood. A piece of the magnet block of an ancient Bainbridge-Jordan type MS constructed by Asada in 1938 is shown in Figure 4. All the other parts have already disappeared. This symbol has a quiet niche in a corner of the Faculty of Science at Osaka University.

F. Mattauch-Herzog's mass spectrograph

A complete discourse on the arrangements of electric and magnetic fields to achieve both velocity and direction focusing for all masses was published by Mattauch and Herzog (13). Many instruments based on these principles have been built and successfully used for both isotopic abundance measurements and general analytical studies. Recently, with the development of position-sensitive detectors, interest in the value of focal plane instruments has been reawakened.

G. Nier's mass spectrometer

Nier had intended to construct a large high-resolution mass spectrometer to compete with the contemporary mass spectrographs (14). The design concept was simple, and the 90" electric field and 60" magnetic field configuration was born out of his familiarity with 60" single focusing instrument (mass separation). His instrument produced a great deal of very accurate atomic mass data, and a number of commercial instruments based on this design have been built. Nier is an ex- ceptional scientist, who was less concerned about ionization of the sample because he had already developed a very powerful EI ion source. I suggest that Nier's mass spectrometer was the second high-performance mass spectrometer.

H. Hintenberger-Koenig and Ewald's mass spectrographs

Hintenberger and Koenig established a method to calculate the ion trajectories and image aberrations up to the second-order approximation and proposed sets of second-order focusing apparatus (15). One of their systems has been used as a commercial instrument (16). The second-order trajectory calculation in an inhomogeneous magnetic field was introduced by Boerboom, Tasman, and Wachs- muth (17). Wachsmuth, Liebl, and Ewald, developed a double-focusing mass spectrograph consisting of a toroidal electric field and an inhomogeneous magnetic field arid showed the possibility of higher mass resolution and of the vertical direction focusing (18). I personally learned very much from them on how to manipulate such very complicated ion optical calculations.

od m E

m a d x tr

al a x Y

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Detector

Toroidal electrode \ k k Homogeneous magnet

k’ I z P i i - 1 2 . 1 . 1 2

r -1 magnet

Figure 5. oscillographic display of 40Ar-40Ca mass doublet.

Ion-optical block diagram of Matsuda’s super-high-resolution MS and

I. Matsuda’s mass spectrometers

1. Super high-resolution mass spectrometer

As a student, Matsuda was engaged initially in operating a Bainbridge-Jordan type mass spectrometer constructed by Asada at Osaka University, and he succeeded in obtaining a mass resolution of 60,000 using a very narrow vertical slit and battery power supplies for the electrode and magnet. These experiences convinced him that an instrument having extremely high mass dispersion was indispensable in order to realize high mass resolving power. He introduced a novel dispersing magnetic field that had no directional focusing and succeeded in obtaining mass resolution of over one million (19) (Fig. 5). 1 was educated on this machine by him. Figure 5 is the ion optical block diagram of the super-high- resolution MS and oscillographic display of very narrow mass doublet 40Ar-40Ca which is only about 200 p mass unit.

2 . Second-order focusing mass spectrometer (1 976)

Matsuda’s next goal was to design a second-order focusing mass spectrometer by introducing a quadrupole lens or a toroidal electric field (20). The effect of the fringing field had been correctly evaluated (21,22) and the computer code ”TRIO”

(23), which had been developed based on the third-order trajectry calculations (24,25), was efficiently used. The prototype instrument (magnetic radius 0.5 m, total path length 3.5 m) was constructed in 1977. Matsuda’s second-order focusing mass spectrometer consists of Cylindrical electric, Electric Quadrupole, and Ho- mogeneous magnetic fields (Fig. 6); CQH MS in its abbreviated form.

Originally he and I intended to use this MS to determine the precise atomic mass of shortlived nuclei produced by a cyclotron. We decided instead to use it for the analysis of heavy molecular weight compounds instead of on-line mass measurement, because we knew that the necessary requirements for both subjects are identical: high transmission and high resolution. We began our application work on this machine. Nowadays, it is employed for cluster studies by using several types of ion sources. Matsuda’s more recent interest was to design a system having high-mass resolution with small image magnification, and high transmission. The system adopted has a QQBQE configuration (26). This instrument will be discussed later.

The purpose, background, new ideas, results, and limits of these pioneering instruments, defined through my personal bias, are summarized in Table I. It may be interesting and instructive to learn that even pioneers had their teachers (background), although the corresponding references are omitted in Table I, and that even high-performance MS of the past had limitations. Such limitations became the trigger for creating new machines. Before ending this section, I should emphasize that although Mattauch-Herzog, Nier-Johnson, Hintenberger-Koenig, and Matsuda type mass spectrometers were historic designs, these machines are engaged in active service. Most commercial sector instruments are designed on the basis of the principles of these instruments. These machines are not ”past” but ”today’s” mass spectrometers.

IV. WHAT ARE TODAY’S HIGH-PERFORMANCE MASS SPECTROMETERS?

Now I would like to discuss what constitutes a “high-performance mass spectrometer” according to contemporary definitions. Figure 7 shows a deformed three-dimensional mass spectrum.

At the beginning of this article, I gave my ”personal” definition of today’s high- performance mass spectrometers as instruments that produce three-dimensional mass spectra. Such a machine is symbolized, as a highly sensitive video camera with number 1. As you have noticed, however, modern high-performance mass spectrometers consist of not only three-dimensional but also very specialized two- dimensional mass spectrometers.

Magnifier 2 points to a “high mass range” requirement. Recently, Barber and Green reported mass spectra of trypsin of about 23 kD by using a sector mass spectrometer (27). On the other hand, I‘D-TOF, LD-TOF can also produce and detect heavy organic compounds of 30,000 dalton and greater. If we in sector MS wish to win the “high mass race,” sensitivity is more essential than resolution, because ion-producing efficiency seems to be inversely proportional to a fourth or fifth power of molecular weight.

Magnifier 3 points to ”high mass resolution” at reasonably high mass range,

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" I / l

resolution -1 2 H i g h k s range

Figure 7. A magnified three-dimensional mass spectrum.

say around 10,000 dalton. With the development of both effective ion sources (FAB, LSIMS) and machines equipped with large magnetic rigidity acceptance (the product of maximum magnetic field strength and magnetic radius), we can determine the accurate mass numbers of isotopically separated peaks of more than 5,000 daltons. This enables us to supply reliable information of the molecular weight of compounds. The requirement with respect to the mass determination accuracy and mass range was discussed in detail in Ref. 28.

Magnifier 4 emphasizes the very high sensitivity detection needed, for example, to find impurities in semiconductor or trace amounts of toxic compounds in our environment. Inductively coupled plasma mass spectrometry and high-resolution GUMS are the recent strategies.

Magnifier 5 underscores the precise quantitative determination of mass-separated ion intensity. Most readers are probably interested in this magnifier. For example, isotope ratio measurement of the elements on the Earth and from other planets and abnormality in clinical diagnosis are two diverse applications of this magnifier.

The requirements for today's high-performance mass spectrometer are identi- fied in another way, bearing in mind the relations revealed by the magnifiers shown in Figure 7. I have classified these into the following five groups:

1. To produce heavy molecular ions 2. To give precise mass determination

3. To measure ion intensities with high precision and high sensitivity 4. To derive structural as well as molecular weight information 5. To operate easily and reliably and to give facile correlation of data

The most important criterion is the development of ion sources capable of producing ions from labile nongaseous organic compounds. The solutions that have so far established themselves are: CI, FD, FAB, LSIMS, PD, and LD. It is no exaggeration to say that the capability of being able to analyze less volatile species has firmly established the present activity of mass spectrometry in various fields of sciences, especially biochemistry. It is a matter of course that the precise mass determination is important. This requirement is related to the magnifier 2 and 3 of Figure 7.

Precise intensity measurements and high sensitivity detection are very important. In most cases, the mass numbers of the samples are known in advance, and the requirement is to determine precisely the ordinates of the mass spectra. This requirement is related to the magnifiers 4 and 5. It should be spelled out that precise intensity together with high sensitivity are requirements especially in isotope ratio and element analysis work. The sample cleaning procedure is pre- requisite for picomole or femtomole analysis of organic compounds. I believe that most mass spectrometrists, especially applications people, are interested in this point. Precise intensity measurement and high sensitivity detection may be the most important of the five requirements for them.

The ability to derive structural as well as molecular weight information from a mass spectrum cannot be overemphasized. For this purpose, several systems have been introduced: GUMS, LC/MS, MSiMS. These arrangements offer three-dimensional mass spectra as defined earlier. This requirement is related to magnifier 1.

Finally, mass spectrometers must have easy and reliable operation, and there should be facile correlation of data. This point is particularly important for the first group of mass spectrometrists I mentioned-the applications people. The solution has been given by the utilization of more and more powerful computers. The development along this path is analogous to the recent developments in light optics culminating with the “all singing-all dancing” automatic cameras that are now on the market. I believe that the developments of cameras will chart the development of mass spectrometers, especially the commercial machines. I think I’D-TOF and LD-TOF may be one step along this path.

I am not sufficiently capable to investigate all five of these subjects and have confined my interests to Topics 2 and 4.

A. Simultaneous fulfillment of high mass resolution, high transmission, and high mass range: a grand scale mass spectrometer ”GEMMY”

Production of heavy molecular ions (ion production) is the first and most difficult barrier to be overcome. I will not touch on this at the moment. Recently, we constructed a grand-scale mass spectrometer that is expected to satisfy the requirements of high mass range and high resolution: magnifiers 2 and 3 simul-

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taneously (29). The fundamental principles of ion optics for the simultaneous fulfillment of high resolution, sensitivity, and mass range are limited by the following four equations:

Mass spectrometer equation M l q = B2p212V

Abbe’s sine’s law xosinao v‘& = xlsinal 6

Q-value concept Q = (xoao. R ) = S,lpl2

Theoretical mass resolution

R = A,/(A,xo + d + A)

where, M = the mass of ion

B = the magnetic field strength

p = the trajectory radius in magnet

V = the accelerating potential

xo = the width of the source slit

a. = the full aperture angle

d = the width of the detector slit

A = higher order aberrations

A, = the mass dispersion coefficient

A, = the image magnification

R = the mass resolution

S, = the area of the envelope of the ion beam in the magnet

The first equation defines the upper limit of mass under the given main trajectory radius p and the maximum field strength B of a magnet. Abbe’s sine’s law means that the product of beam width x , aperture angle a, and accelerating potential V is constant. Then better beam character is realized by increasing V . The Q-value concept means that the product of sensitivity (xoao) and mass resolution ( R ) is proportional to the area (S,) divided by the radius (p). If higher sensitivity and mass resolution are required simultaneously, a larger area S, is necessary. The theoretical mass resolution is approximately proportional to the ratio of A,/A,. Mass dispersion A, is proportional to the radius p.

, 0 I r n 2 m 3rn 4 m 5 m 6m

Figure 8. Ion-optical block diagram of "GEMMY."

The conclusion derived from these arguments is very simple: A grand-scale machine is indispensable. We adopted the QQBQE geometry originally proposed by Matsuda (26) for our instrument, and modifications were made to facilitate the size and machining of the components. We christened this machine GEMMY (Grand-Scale Mass Spectrometer for Biomolecule Analysis). An ion-optical block diagram is shown in Figure 8.

The specifications of "GEMMY" are as follows: Total path length: 7.6 m Magnet radius: 1.25 m Max magnetic field: 1.8T Mass range: 12,500 Da at 20 kV, 25,000 Da at 10 kV, 50,000 Da at 5 kV

Figure 9 illustrates the whole instrument. The machining and construction were done in collaboration with JEOL (Tokyo) and the Kobe Steel Company (Kobe). The size of GEMMY compared to other important instruments on the same re- duced scale is illustrated in Figure 10. It is quite reasonable, I believe, to assume that sector mass spectrometers are going to grow bigger and bigger proportion- ately as the molecules of interest grow heavier and heavier. Much bigger instruments were also constructed at various institutions around the world, mainly for precise atomic mass measurement. GEMMY seems tiny among them (Fig. 11).

To see more clearly the development of ion optics in mass spectrometry, we constructed on paper four instruments with the same magnet radius: 1 meter. If

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4 F i + Aston

b Dempster

Bainbridge -Jordan

Mat tauch c f l -Herzog

''- CQH (Matsuda)

f i Nier-Johnson T

0 3 111

Figure 10. The evolution of mass spectrometer design.

we assume the same source slit width (100 pm) and detector slit (19 pm), we can simulate the image shape at the detector profile plane by using the computer code BEIS (30) and estimate the theoretical mass resolution. Mass dispersion, which means the distance between the peak tops of a mass doublet, is of nearly similar magnitude because we assume the same magnet radius (see Fig. 12). On the other hand, image magnification and higher order aberrations have changed considerably, contributing greatly to improved mass resolution and transmission.

In Figure 13, we see the beam envelopes of four mass spectrometers both in the horizontal and vertical planes. In older designs, only cylindrical electric sectors and homogeneous magnetic fields were used, which lack focusing action in the

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Derrick

1987 1980

k. ,<.J White 1972

1961 1961 0 5 It1

Figure 11. Examples of grand-scale mass spectrometers.

Mass resolution

Mattaurh-Herzog 3600

U ' Nier-Johnson ' 5200

9800 111 CQH (Matsuda) I

Figure 12. slit condition.

Theoretical image shapes of four mass spectrometers under the same

Horizontal Vertical

Mattauch-Herzog

CQH (Matsuda)

Figure 13. Beam envelopes of four mass spectrometers.

vertical direction. Satisfactory beam transmission cannot be expected by using these combinations, especially on a grand-scale instrument. Introducing an electric quadrupole lens greatly improves the vertical transmission as shown in the figure. The function of this type of lens is not only to focus the ion beam in the vertical direction, but also to diverge the beam in the horizontal plane. This is a particularly important point because the ion beam entering the magnet is dis- persed more widely, thus causing it to be focused on the detector at a much sharper angle. The image magnification is then small, and a higher mass resolution may be expected. In other words, the area of the envelope of the ion beam in the magnet becomes large, and a higher mass resolution is expected from the Q- value concept (31). It should be noted that there is another way to obtain the large Q value by using an ion source with a short focal length to open up the beam in the magnet (32).

B. Mass spectra obtained by GEMMY

Some preliminary results obtained on GEMMY will now be presented.

1. High mass spectra at low mass resolution

A spectrum of CsI clusters up to m/z 48,000 at an acceleration voltage of 5 kV is shown in Figure 14. The mass difference between two peaks is 260 mass units. The discussion of the magic number theory and undulation of mass distribution has been covered in elsewhere (33).

A mass spectrum of silver cluster ions up to m/z 20,000 is given in Figure 15. The acceleration voltage was 10 kV. The magic numbers are again clear, and are

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P 20000 25000 30000 35000 40000 45000(m/d

70 80 90 100 I10 120 130 140 150 160 170 180

Figure 14. Mass spectrum of CsI clusters.

explained by the closed shell models derived by the analogy to nuclear structure (34).

We are also interested in detecting heavy molecular ions: say 10,000-30,000 daltons in the low resolution mode. Barber and Green showed high mass spectra, such as for trypsin, by sector MS (27). Hakansson et al. also gave PD-TOF mass spectra of these compounds (35). At the moment, however, any group would like to quote Dempster “The experimental difficulty is to get the rays, and this is the matter now under investigation.” We intend to increase the acceleration voltage in order to get a better ion extraction efficiency.

2 . High mass resolution at relatively high mass range

We checked the mass resolution by taking a normal EI spectrum of a phosphazine compound, which was important for me from the following two points of view:

Figure 15. Mass spectrum of silver clusters.

A Perfluoroalkyl phosphazine

3535 3536 3537

B Perfluoroalkyl phospholonitrilate

Figure 16. (A) EI mass spectrum of phosphazine compound by "GEMMY." The- oretical mass resolution: 28,000. Experimental mass resolution: 24,300. (B) Mass spectrum of phosphazine compound. Reported by Fales and reprinted from Ref. 36 with permission.

First, we needed to establish agreement between the theoretical and experimental mass resolution. Experimentally, it is 24,300 and theoretically 28,000 with 100 pm source slit width (Fig. 16). They agree quite well. Of course, if the slit width is less, higher resolution should be achieved. For example, a slit width of 10 km should give 280,000, and 1 pm should give 2,800,000. For this type of performance, however, the stabilities of all the component parts of the instrument must be controlled much more rigorously. The principal purpose of GEMMY is not super high resolution, but simultaneous achievement of high resolution and high mass range. We have not pursued the super high resolution experiments up to now.

Second, we were interested in making a comparison between this spectrum and a similar spectrum taken by Fales of NIH in 1966 (shown in lower part of Fig. 16) (36). Obtaining a similar spectrum has been my goal for the last 20 years. In 1979, we could take the mass spectrum of polystyrene up to 12,000 Da by field desorption with silicon emitters and could exceed his mass range (37). Now by using GEMMY, we can obtain the EI mass spectrum of the phosphazine compound of around 3,500 Da at much better resolution.

The mass spectrum of a protected RNA decamer was obtained to illustrate the capability of the precise mass determination of each isotopically separated peak of relatively heavy compounds. Figure 17 is the mass spectrum of a protonated RNA decamer, which was synthesized by the solid-phase method, with a sus- pected molecular formula of C266H277097N43PloCllo (38). As is clear from the formula, the compound contains a number of chlorine atoms, thus complicating the

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\ A’’’ ‘)

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c j - . , . , . , , 6198 6192 6194 6196 6198 6200 6E02 6204

Figure 17. Mass spectrum of synthesized RNA lOmer (Tr-GAUGAUGCGCP).

molecular isotope pattern quite considerably. Theoretically, the most intense peak wiII occur at 6197.3. Experimentally, it was found to be 6197.6.

Figure 18 shows the development of insulin mass spectra during the past 6 years. The first spectrum A shown by Barber et al. in 1982 was most impressive for me. From these six mass spectra, we can see that mass resolution has improved very much.

Unit mass resolution is important for observing the isotopic clusters. The resolution improvement in going from D to F in Figure 18 gives no additional information. If the resolution could be increased to 1,000,000, then fine structure due to the different combinations of various isotopes could be seen, as was discussed in Ref. 28. Developing mass spectrometers with this resolving power will require new ideas, effort, and money. I don’t believe this is a necessary development in the coming 10 years. An instrument giving unit mass resolution at miz 7000 is sufficient for today’s research.

5 8 0 0 5 8 2 0

Figure 18. Improvement of insulin mass spectra over time. (A) From Ref. 39; (B) from Ref. 40; (C) from Ref. 41; (D) from Ref. 42; (E) from Ref. 43. All figures reprinted with permission.

If the molecular weights of interest become heavier than 7,000, then low-resolution mass spectra like spectrum A( Fig. 18) are useful for giving chemical molecular weights. The reason for setting the boundary level at 7,000 is that for molecular masses exceeding this, monoisotopic peaks become swamped by the background noise generated by FAB and LSIMS ionization techniques. Of course, the chemical molecular weight can be determined from a spectrum in which the isotopic peaks are merged; however, we cannot distinguish narrow mass doublets. We often have to distinguish samples which contain Glu or Gln, and Asp or Asn, which differ by only one mass unit. This is one reason why GEMMY is used in at least the unit mass resolution mode at a mass range of over 5,000.

228 MATSUO

I4 i.-$er-Oln -01~-1 h r - C h . - T h ~ S o r - A ~ P - T ~ r - S e ~ l ~ ~ - l v r c4- -cz- - c*-J

L e u - A s P -Ser-Arg-Arg - Ah-Oln - A a p C h . - V a l - O In -1rp-Leu-Met-Am-Thr-OH t

1 I I I I

Figure 19. FD mass spectra of chymotryptic glucagon (0) and successively Edman degradated peptide fragments (1). Reprinted from Ref. 44 with the permission of The Petroleum Institute, London.

C. Ability to derive structural and molecular weight information: Structural analysis of peptides by mass spectrometry

I wish now to discuss the third point of today’s high-performance mass spectrometers; that is, the ability to derive structural as well as molecular weight information as indicated by video camera 1 in Figure 7. It has always held a certain fascination for me. As I said in the beginning of the article, I belong 10% to the characterization group and 20% to the ”novel” compounds group. I have been engaged mainly in structural analysis of peptides by mass spectrometry in the following ways:

1. Determination of precise molecular weights of peptide mixture 2. Combination with Edman degradation 3. Characterization of protein variants 4. Sequence determination by MSiMS technique

Figure 19 is the FD mass spectrum of chymotryptic glucagon taken by using a silicon emitter, and was reported on at the 8th International Mass Spectrometry Conference held at Oslo, Norway in 1979 (44). We also proposed the combination of mass spectrometry with Edman degradation, which has become a useful technique for peptide mixture analysis (45). Peptide mixture analysis by MS has become very popular, especially since FAB and LSIMS ionization methods were

Figure 20. Mass spectrum tryptic hemoglobin (Y chain.

established. These works were born as collaborative efforts with the Shimonishi- Izumi group Institute for Protein Research of Osaka University.

Next, we focused on a real medical problem. The characterization of protein variants, especially hemoglobin. The SIMS mass spectrum of a tryptic digest of hemoglobin (Y chain is given in Figure 20. The molecular weights of most tryptic peptides are less than 5,000, and GEMMY is particularly capable in this range. The sample required for one measurement is less than 1 nmol. We have been collaborating with Drs. Wada and Hayashi and their group of the Osaka Prefecture Medical Center in this project.

Table I1 is a listing of hemoglobin variants characterized by mass spectrometry. We characterized 13 variants. Five of them were unknown, and the other eight were found to be already reported. The strategy of characterizing hemoglobin variants by mass spectrometry will be presented in a later article in this journal (46) *

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Table I1 Hemoglobin variants classified by mass spectrometry Variant Components MIZ Status

1 Hb Meilahti p 36PrmThr 1 2 7 b 1278 (new variant) 2 HbFIzumi Ay 6Glu-Gly 191G1847 (new variant) 3 HbFFuchu Gy 21Glu+Gln 1316.1315 (new variant) 4 Hb F Minoo Cy 72GlypArg 101-688,446 (new variant) 5 HbA2Honai 6 90Glu-Val 1507-21477 (new variant) 6 Hb Shimonoseki (Y 54Gln-Arg 1833+1634 (found before) 7 H b U b e I I a 68AsnjAsp 299b2995 (found before) 8 Hb Hikari p 61LysjAsn 246,412-625 (found before) 9 Hb Providence p 82Lys+Asn,Asp 1669-+2858,2859 (found before)

10 Hb Riyadh p 120Lys-Asn 908,137b2253 (found before) 11 Hb F Iwata Ay 72Gly-Arg 1016.688,446 (found before) 12 Hb F Yamaguchi Ay '80AspAsn 7 4 k 7 3 9 (found before) 13 Hb Az Indonesia 6 69Gly-Arg 1669-.1400 (found before) 14 Synthetic variant cx 42TyrjPhe 183-1817 (verified) 15 Synthetic variant (Y 42TywHis 183h1807 (verified) 16 Prealbumin variant 30VakMet 136-1398 (diagnosed)

A mass spectrum of a tryptic digest of the abnormal hemoglobin p chain (Hb Nishiyama) (Fig. 21), reveals a specific mutation. A mass shift of 58 Da was found. Thus, two types of amino acid mutations are expected; namely: Asp to Gly or Glu to Ala. There are three possible candidates for the corresponding fragment. Although this is a beautiful spectrum, we were unable to locate the mutation site without additional information. Strategies are available to solve this ambiguity:

1. Further digestion using other enzymes 2. Combination with manual or automatic Edman degradation

MS/MS methods, however, are much more rapid and informative.

f e 801 1

1 8 1 9 2 0 2 1 2 2 2 3 2 4 2 5 26 2 7 2 8 2 9 30 M+H

TP3LNORHAL) V N V D E V G G E A L G R 1 3 1 4 Hb (NISHIYAMA) G A A 1 2 5 6

d 2000

rrr! c

M / i 00

Figure 21. Normal mass spectrum of tryptic Hb-P variant Nishiyama.

0 1 111 I 1

Dv tvr tor -- r--

D. Four-sector mass spectrometry

Now, allow me to touch briefly on tandem mass spectrometry. Figure 22 shows the early Tandem Mass Spectrometers developed about 30 years ago by White and Collins (47) and Futrell and Miller (48). The ensuing era brought reversed geometry instruments by Maurer et al. (49) and Wachs et al. (50).

The modern tandem mass spectrometer was born from the pioneering works of Boyd and Beynon (51), Bruins (52), Schlunegger (53), McLafferty (54) and their colleagues. High-resolution selection MS/MS studies by using three-sector instruments were first reported by Gross et al. (55) and the MS/MS strategy for determination of protein structure by using four-sector instruments was initiated and established by Biemann and co-workers (42,56). McLafferty’s expectations for tandem double-focussing MS, which I heard at the 7th International Confer- ence held in Florence in 1976, have now been realized in the instruments of today (Fig. 23). McLafferty’s instrument is shown in the upper part of this figure. The lower figure is the tandem MS at MIT(HXllO/HX110) (57), which was used to characterize the hemoglobin variant Hb-Nishiyama.

An MS/MS spectrum of the abnormal peak of Hb-Nishiyama was obtained (Fig. 24). The spectrum was taken by Costello using the MIT machine, and the inter- preted peaks are indicated by the annotations. This spectrum shows without ambiguity that the variant occurs at the 22nd position, with a Glu to Ala substi-

232 MATSUO

Figure 23. Modern tandem mass spectrometers. (A) The Cornell double-focusing mass spectrometer (from Ref. 54); (B) The JEOL HXllOiHXllO mass spectrometer (from Ref. 57). All figures reprinted with permission.

tution. This mass spectrum is, for me, one of the most beautiful that can be obtained by today’s high-performance mass spectrometers.

Very recently, we developed an additional function of four-sector MS, which enhances mass resolution without decreasing beam intensity, in a cooperative research project with Biemann’s group (58). In other words, we use a four-sector MS as a single double-focusing MS with higher mass resolution. The upper spectrum in Figure 25 is a FAB spectrum of Mellitin that is obtained by using MS I only. The lower spectrum was obtained using four sectors (MS I + MS 11). From the ion-optical calculation, a resolution improvement factor of 2.5 was expected, and 2.4 was obtained experimentally. I believe this operation is suitable for array detectors (59), or for acceleration voltage scanning. We can determine the molecular weight more precisely if we can separate clearly the isotope peaks.

The key function for these two operation modes, which are MS/MS and en- hanced mass resolution, comes from the introduction of the quadrupule triplet at the interface area between MS I and MS 11.

x T N X

0 0 - 0 0

0 0 00

f 33NVaNflEV 3AIlVl3tl

0 0 I\

0 0 In

0 0 -t

0 0 I?

0 0 c-4

234 MATSUO

Figure 25. eration. Reprinted from Ref. 58 with permission.

Mass spectrum of melittin by two-sector (A) and four-sector (B) op-

V. FINAL REMARKS

I would like to conclude by saying that today's high-performance sector type mass spectrometer is an appropriately sized tandem double-focusing-mass spectrometer, although we must not forget about the prototype specialist machines such as grand-scale mass spectrometers for basic investigations. A tandem system satisfies almost all the requirements that I mentioned in Section IV of this article.

In the process of preparing this article, I reviewed the pioneering instrumentation and felt that the principal guideline for the development of mass spectrometers was very conservative: always high resolution, high sensitivity, and high accuracy. The objectives of mass spectrometry, however, have dramatically changed from original investigations of the electron to now looking at complex molecules. It is fair to say that the current objective (applications and developments of instrumentation) have stimulated each other, and the interaction has borne fruit.

I hope the reader will agree with my argument that concrete objectives come first. Then, new high-performance mass spectrometers will be created accordingly. Before we discuss what are the necessary requirements for high-performance mass spectrometer, we should discuss what kind of study do we want to

do. This will act as a motivating force for developing the future high-performance mass spectrometers.

VI. ACKNOWLEDGMENT

My studies in mass spectrometry have been supported and encouraged by senior professors, and I would like to express my sincere thanks to them. I am very grateful to my contemporary colleagues: Dr. Y. Wada, Dr. A. Hayashi, Professor Y. Yamamura, who sparked my interest to the application of mass spectrometry as a technique; Dr. I. Katakuse and Dr. T. Sakurai for their effort of achieving our present mass spectrometric techniques. I am indebted to Pro- fessor K. Biemann for his kind support in investigating a four-sector mass spectrometer. I thank Dr. Mike Morris of UMIST England for assistance with English. Financial support for constructing ”GEMMY” by the Japanese Ministry of Edu- cation is gratefully acknowledged, and technical support by the Japanese mass spectrometer companies is gratefully appreciated. Above all, I would like to extend my gracious thanks to Professor Matsuda who was my teacher, my supervisor, and my strongest competitor all at the same time.

6. 7. 8. 9.

10. 11. 12.

13. 14. 15. 16.

18. 19. 20. 21. 22. 23. 24. 25.

VII. REFERENCES

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